In the mind of Gould



Part one of his second recording of the Goldberg Variations (1981)-the more soulful of his recordings. The 1954 recording is a fierce attack, and  serves as a stark contrast to the later performance (below) – after it’s been rattling around in his head for almost 30 years.


Posted by on November 20, 2015 in Uncategorized


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Cancer Immunotherapy Continued: Non-transgenic T Cell Therapy

A number of adoptive T cell therapies are being examined for cancer treatment including isolation and culturing tumor infiltrating lymphocytes (TILs), isolating and expanding a specific T cell or clone, and generating novel T cells with chimeric receptors designed to target tumor cells and provide robust activation signals to the T cell. 1,2

Recently, I wrote a short essay about CAR T Cell therapy and how this therapy uses genetically modified T Cells to generate a large number of your own cells, capable of targeting tumors bearing a known antigen (e.g. CD19 as a Lymphoma marker).

T Cells are one of the immune system’s specific attackers, capable of recognizing cells bearing specific antigen only. They are engaged and activated via interactions with APCs presenting antigen bound to MHC molecules as well as other ‘secondary’ signals.  For a more complete description, see

In the case when the T Cell recognizes the antigen, it proliferates and activates if provided sufficient secondary signals in addition to TCR stimulation. In the absence of recognition, the T Cells will not stably bind the APC and therefor not receive sufficient signaling to activate.

T Cells ‘see’ antigen through presentation in the context of MHC molecules on the surface of Antigen Presenting Cells (APCs)

T Cells ‘see’ antigen through presentation in the context of MHC molecules on the surface of Antigen Presenting Cells (APCs)

Some benefits to that therapy include incorporation of a well-designed chimeric antigen receptor capable of providing normal T Cell Receptor (TCR) signals as well as signals from co-receptors required to generate mature effector cells. Because this construct targets the CD19 molecule directly, it does not require processing and presentation of antigen via MHC I by the tumor cells (important because one strategy tumor cells use to evade immune detection is to down-regulate MHC I). Using the patient’s own cells also means that immunosuppressive drugs aren’t required to prevent the body from rejecting the therapy.

One drawback though, is that the construct is made synthetically and can only include antibody binding regions specific to known cell surface antigens. So, if you know the cells you want to get rid of, and you can make an antibody to bind those cells preferentially, CAR T Cells are a good therapy for you.

Using Non-Transgenic T cells, similar effects can be obtained with an inverse set of pros and cons. Because this therapy does not utilize chimeric receptors, cells specific for a known  antigen aren’t singularly generated. Rather, a diverse array of cells is generated against tumor targets without requiring the isolation and characterization of one particular antigen. As opposed to the CAR T Cells these cells can only interact with target cells that present antigen via their MHC I molecules, which can be a drawback in situations where the tumor cells have downregulated antigen presentation molecules.

The Non-transgenic cells used may be generated in several ways. One method includes the harvest of tumor tissue from the patient, followed by killing these cells and re-injecting them (possibly in the presence of an adjuvant) to illicit a targeted immune response. 7-10 days later, peripheral T Cells enhanced for target specificity by the vaccine can be harvested and amplified outside of the body. In this way, cells can be amplified to numbers far outpacing what might be found in the patient, while also providing additional activation signals to promote effector cell development.

A second way of utilizing non-Transgenic T Cells in therapy is to isolate only those T Cells found to be actively invading the tumor. This biases toward cells already selected for by the immune system that may simply not be able to keep pace with the tumor’s growth. Ex vivo amplification can provide these cells the boost in numbers required to tip the balance in favor of the patient.

Screen Shot 2015-11-15 at 12.08.22 PM

Coupling any of these therapies with other treatments, such as the human monocloncal antibody anti-CTLA-4 (ipilimumab) 4, can further support T Cell efficacy – in this case by blocking checkpoints used to dampen the immune response following a period of activation. In healthy patients, these checkpoints allow the immune system to revert to a state of homeostasis once pathogens have been cleared. In cancer patients, the tumor may not yet be eradicated before checkpoint molecules begin to dampen the response. By interrupting these, the window during which T Cells are most effective is widened — at least in some patients.

This article has been cross-posted on Medium

A Few References:
3. My Medium Post

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Posted by on November 15, 2015 in Uncategorized


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extremely satisfying to watch


actually, this one is even better. A fugue is just as much a piece of visual art as it is music.

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Posted by on November 14, 2015 in Uncategorized


When was the last time an argument changed your mind?

I mean, really.

Imagine you are watching a debate for the presidential candidates and you go into the debate with certain opinions on how things should be run – say: tax code. Then, after sitting and watching the candidates outline their rationale (right?! I know I’m reaching here) you think to yourself, ‘huh. Well, that guy just changed my mind.’

Does this ever really happen?

Fairly certain this guy has never been persuaded to a different opinion

Fairly certain this guy has never been persuaded to a different opinion

Can people who believe in a ‘flat tax’ be persuaded that a ‘progressive tax’ structure is more fair and more worthy of their support? (I threw in the ‘and’ there because you can be shown the rationale for something and agree with it without changing your position)

Can proponents of a ‘pathway to citizenship’ be convinced that it’s simply too impractical to actually be enacted?

Can pro-lifers be converted to pro-choice by the right argument?

(as a side note, I wrote the above statements in a completely arbitrary manner, because I recognize that people also seek out ‘echo chambers’ for their own ways of thinking, which may be a part of the problem as a whole. Anyway, I don’t mean to deter a reader because they see words like ‘pro-choice’ or ‘pro-life’.)

Kepler could have applied himself better...

Kepler could have applied himself better…

Sometimes I question whether the Greeks were just wasting their time spending all that energy thinking about rhetoric. They didn’t persuade the Romans to stay out of their lands and to not steal their whole pantheon of gods. Maybe if they spent a little more time practicing their phalanx formations and a little less worrying about whether there was really a place filled with Perfect Forms (I’m looking at you, Plato) that we vaguely remember from before the time we were born, they might have effected a more sturdy border guard.


I changed my mind today about something. (I’m still working on changing it about some other things that would make my life easier, but I’m off to a good start) I got an email pointing me to the following post by Brett Berry on Medium this morning. 5 x 3 = 5 + 5 + 5 Was Marked Wrong
My first reaction was to be upset with the teacher who gave this kid points off for correct answers. I opened the article in order to satisfy my own desire for hearing an echo chamber of my thoughts only to find that the author took a different stance.

I kept reading because I was determined to write a comment to express my ire – but, you know, wanted to make sure that I could point out the best examples of the author’s flawed thinking first. I first saw that he was making a reasonable argument, but felt like it was still wrong. Then I saw how his examples supported his way of thinking and was starting to lament that he was making it more difficult for me to undercut him. Finally, he added that, depending on the order that things were taught, the answer could be considered correct under some circumstances, but that it was better to teach the meaning of the maths stepwise in order to law the proper framework for future lessons.

I give up. You win, Math Guy.

Not only did you change my mind on this issue, but you also laid the framework for me to re-examine my whole approach to Common Core.


Posted by on October 31, 2015 in Uncategorized


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A Short Film About Adjunct Educators

I just stumbled upon this short film today. It discusses the issue of adjunct instructors teaching at community colleges and even state universities. If you are unaware of what an adjunct is, it’s a part time teaching position that pays instructors on a per-course schedule. Taking an adjunct position in the past was a mixed blessing for me. On the one hand it enabled me to step into a teaching position with little barrier to entry, but on the other, the pay is extremely low and jobs come with no benefits.

To make matters even more complicated, the people for whom I was directly working had no power to alleviate this situation as they were mandated to schedule and fill certain courses without the funding to do it properly (by that, I mean with full time faculty). While I was settling for a sub par wage, they were dealing with the uncertainty that their instructors would come back for another semester. In fact, since most contracts were not finalized until halfway through the semester or later, it is not unreasonable that an instructor might back out of teaching a month or two into a course in order to take full time employment somewhere else.

Given this situation, very few instructors are able to support themselves on these wages. Those who try, struggle. Most only teach because they enjoy it. So, the next time you enroll in a college / university class and are writing a good-sized check, remember that your education is being provided by someone’s hobby and hope that their interests don’t suddenly change.

The film, Professors in Poverty:

After the film, check out the website to learn what you can do to effect change.

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Posted by on October 29, 2015 in Uncategorized


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Back from the Dead

Halloween seems like a good time to resurrect old blog posts that haven’t seen the sunlight for several years. Creeping out of the tomb is my first blog post about Genes, DNA, Memes, and GMO foods. Rather than post it here, I decided to post it over on my Medium site to see if it can catch some new eyes.

Take a look: Linked Memes

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Posted by on October 26, 2015 in Uncategorized


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The Skinny on Cancer Immunotherapy: focus on CAR T Cells

Screen Shot 2015-10-22 at 9.47.44 AMOne of the more interesting modern therapies being used to fight cancer aims to coax, or engineer a patient’s own T Cells to fight disease.
In very basic terms, the principle is not dissimilar to vaccine strategies used against infectious disease. That is, they direct and boost the patient’s immune system against target cells. One reason vaccinations have been so successful in fighting disease is that they leave much of the hard work to nature – the same nature that has been keeping you and your ancestors healthy enough to successfully reproduce for millions of years. Give the immune system a push in the right direction with a well designed, safe vaccine and the body does the rest leading to (at least theoretically) life-long protection. At this point, the most limiting factor to how long protection lasts is because we live so much longer than humans have ever lived before.

William-Coley_206x236Immunotherapy against cancer has been an area of interest since the 1890s, when William Coley observed that cancer patients who had infections at the site of surgical resection fared better than those without infections. Rather than dismissing this observation as uninformative, he speculated that the immune system plays an active role in preventing or regressing tumors.

In fact, the immune system is constantly performing ‘immune surveillance’ to prevent newly-generated cancer cells from developing into tumors. Direct evidence for this involves ‘knocking out’ elements of the immune system and watching for cancer. As predicted by the theory, immunodeficient animals develop spontaneous tumors at a higher rate, and earlier than do immune-competent animals.

The pudding: (from :

Evidence for Immuno Surveillance

Evidence for Immuno Surveillance

But vaccinations used against infectious diseases are given before the patient is infected (known as prophylactic vaccination).

How can we immunize people against all the cancers that may crop up in all their various forms?

The answer is – we don’t. In the case of cancer, we perform vaccinations ‘therapeutically’, or after disease has started. Otherwise there really would simply be too many possible targets.
So, we wait, and help the body to fight the challenges that actually do arise.
A number of methods have been developed and tested to accomplish this, here, I want to specifically address a personalized therapy that takes cells from the patient, ‘aggravates’ and expands them, and then re-infuses them into the same patient.
Currently, there are several ways this is being done with various outcomes.

One method involves immunizing the patient against killed cancer cells isolated from the themselves (via surgery), then harvesting the reacting cells and expanding them to numbers much higher than those reached in vivo, and then re-administering to the patient as a jump-start to immunity. The advantages are that these immune cells are ‘self’ and therefore do not have to be ‘matched’ to the recipient a la transplantation surgery. It is also possible to remove any regulatory cells (T regs), that often impair immune responses, prior to re-administration.
A more engineered response has been investigated by investigators such as Carl June, of the Abramson Cancer Center at the University of Pennsylvania. These cells, known as CAR T Cells express ‘Chimeric Antigen Receptors’ directly target tumor cells using transgenic antibodies that incorporate the intracellular signaling domains of up to three immune-activating receptors. See the illustration below for details of this receptor’s design (taken from ‘Breakthroughs in Cancer Immunotherapy webinar by Dr. June )
Screen Shot 2015-10-21 at 7.20.04 PM
In the case of CAR T Cells, most have been made to fight B Cell Chronic Lymphocytic Leukemia (B Cell CLL). These cells are a good test case for the technique for a number of reasons, including the fact that they uniformly* express a marker called CD19 on their surface and also because they are a ‘liquid tumor’ – meaning that the cancer cells are individual cells moving through the body (at least many are). Treatment of solid tumors can bring added complications such as the need to infiltrate the tumor in order to find target cells.
As I said, CD19 is a common protein expressed on these cells. Therefore, at least the CAR receptor part is standardized between patients – this is the piece that is added to cells transgenically so that they will bear a receptor known to engage the target cells with high affinity. Because it must be added to the patient’s own cells, this is accomplished using a viral vector that infects the T Cells in culture and provides the DNA required to make the receptor. (In case you’re worried about the virus, these are engineered to only infect the first cell they encounter, they cannot reproduce themselves and continue an infection)
So, let’s walk through it:

Screen Shot 2015-10-21 at 7.20.04 PM
1. Blood cells are isolated from a patient
2. T Cells are purified (i.e. isolated)
3. T Cells are infected with virus in culture.
4. T Cells grow up with the chimeric antigen receptor expressed on their surface
5. These cells are then re-injected into the patient via I.V. drip over about 30 minutes time.
6. Let the cells do the work

Screen Shot 2015-10-22 at 10.33.53 AM
This therapy has an impressive track record so far with studies with success rates from ~60%- 90% of patients responding and remaining disease free for years (Maude et al).
Following the initial infusion of cells, CAR T Cells proliferate in vivo to very high numbers and can even form immunological memory cells to come to the rescue in the event of a relapse.
So, what next?
A number of startup companies have emerged to tackle the logistics of bringing this type of therapy – an extreme example of personalized medical care – into being. Unlike traditional drug therapies where a single compound is mass produced and distributed world-wide, each patient must have their own cells processed and returned to them for infusion. This therapy is much more of a service, and as such, will require physical locations across the country that can manage the handling of cells.
The up side, however, is potentially transforming fatal diseases into manageable ones with a high quality of life after therapy.
Just ask Emma:

*Well, most do, anyway.


Posted by on October 22, 2015 in Uncategorized


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