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New model for infection and health

David Schneider from Stanford University has suggested an interesting way to look at the delicate relationship (Diagram below) between infection and the degree of health last week in Chicago.

david 2During an usual infection (blue line), whether it is bacteria or virus, when the infection load increases (1), your health status gets worse. At some point, your immune system gets fully activated (2) and begins to fight off the infection (3). When you are recovered from the infection, you are at point 4 on the diagram.

For some unlucky patients, their immune system may be dysfunctioned, due to genetic predisposition or chemotherapy or etc. They can end up as represented by the red line that shows an increase and uncontrolled infection load, which results in death at the end.

For immune dysfunctioned individuals with bloodstream infection of staph aureus (such as people with HIV, or who recently gone through chemotherapy or who with a certain tissue malignancy), the mortality can be found concentrated between 30 to 90 days after first getting hospitalized. Thus, it suggests that the immune defense against the first pathogen assault was not compromised, but the defense is not capable to control and prevent the “re-growth” of the pathogen.

david 3This diagram above nicely lays out the proposed infectious cycle of staph aureus infection in bloodstream in immune dysfunctioned patients. At stage 1, the immune system is activated. At stage 2, the immune system is activated and begins to control and fight off the infection. At stage 3, the immune system somehow shuts down or unable to continue, and the bacteria begins to increase. At stage 4 and beyond, the bacteria load continues to increase, which results in death.

The conventional way to look at this relationship is to plot infection load against time. This new model enables us to ask questions, such as “does a prior infection of pathogen a give me a heightened health status after recovery?”, and “How do we access the status of health in a clinical setting?”.

Immunotherapy: T cells vs Leukemia

Image credit: Singularity Hub
Image credit: Singularity Hub

Cancer immunotherapy, named Science’s “breakthrough of the year” 2013, is the manipulation of the patient’s own immune system to combat a disease. Since its initial beginnings in the late 1980s cancer immunotherapy has grown to be one of the most exciting prospects in biomedical science today. The first treatment of this type came in the form of an antibody against cytotoxic T-lymphocyte antigen 4 (CTLA4), a protein on T cells that is known to reduce the T cell response when active. Blocking this function with an antibody it was hypothesized, by immunologist James Allison, may enhance the immune response and let it properly attack cancerous cells, as the researchers then demonstrated in mice. This idea was developed by a small biotech,Medarex, which was then bought by Bristol-Myers Squibb. It wasn’t until 2010 that the company could report that their antibody had increased the life-span of patients with metastatic melanoma from 6 months to 10 months, the first treatment shown to extend life in this form of cancer trial.

Another aspect of immunotherapy, aside from antibodies and other biologics, is the manipulation of T cells directly harvested from the patient to be active cancer hunters when re-administered. This work, a form of cellular therapy, was pioneered by Steven Rosenberg and has been followed up on by a multitude of researchers, commonly looking at types of blood cancer due to its accessibility in comparison to cancer of other areas of the body. In 2010 Rosenberg described chimeric antigen receptor (CAR) therapy, in which a patients T cells are genetically engineered to express a receptor that allows them to target specific cells, in this case cancerous cells. This is also referred to as T cell “re-education”.

Now a team of researchers at the Memorial Sloan-Kettering Cancer Centre in New York has published new data from a study using their CAR, 19-28z. This specific CAR targets the marker CD19, also known as B-lymphocyte antigen, which is present on another type of immune cell, the B cell. These cells are normally involved in antibody production and in providing one type of the long-lasting immunological memory, but as with many cell types when things go wrong they can become malignant, cancerous. Adult B cell acute lymphoblastic leukemia (ALL) is a form of blood cancer caused by malignant B cells that have yet to fully mature. Importantly therapies targeting B cells expressing CD19 would not affect fully matured B cells, or plasma cells which do not express CD19. As mentioned previously these cells are responsible for the vital mechanisms of antibody production and immunological memory, hence these hugely important aspects of the immune system would survive treatment with CD19-targeting therapies, whereas (hopefully) the cancerous CD19 positive cells would not. Interestingly, other studies have shown that CD19 may in fact be directly involved in the development of some cancers making the choice of targeting this molecule even more attractive.

In their latest study the researchers showed that, in a group of 16 patients, 88% showed a complete response to the CAR therapy. This means that 14 of the 16 were able to reach complete remission and then begin hematopoietic stem cell transplant to maintain this state. These patients had previously relapsed from remission after standard treatments and so had been offered this treatment instead of salvage chemotherapy, which is only effective in 30% of relapsed ALL patients. These results build on the 2013 data by the same group that first showed that 19-28z CAR was well-tolerated and showed significant ability to treat relapsed ALL. Unfortunately there are some adverse risks with this treatment. Some patients have shown markedly increased levels of serum cytokines in what is known as severe cytokine release syndrome (sCRS). This is treatable with corticosteroids amid other therapies but it is essential that research is undertaken to identify those patients who are likely to develop this issue. CAR therapy is at its heart a personalised medicine and so understanding these adverse effects and their likelihood between different people is of great importance. Adverse effects aside, the researchers and the data, which speaks for itself (88% v 30% seems like an obvious choice to me), claim that this treatment is deserving of moving on to phase II trials. Steven Rosenberg said in a paper in 2013 that anti-CD19 CAR T cells could become the standard therapy for some B cell cancers and it seems that this latest data supports this. It has been a long road for cancer immunotherapy but with results like this from an ever more popular field of research, one can hope that soon there will be multiple therapies of this type advancing to the point where they become the standard-of-care and herald a new era of personalised cancer treatment.

Brief Guide to PhD Applications

Applying to doctoral programs can be an extremely stressful task, especially since each university has its own guidelines and requirements. Given the wide-ranging requirements by different programs, it is impossible to provide an all-encompassing guide to applications. This short guide, however, is an attempt at providing assistance to those interested in pursuing higher education. I treated my applications as a “course”. That is, I spent an average of 10-15 hours per week working on applications, writing, re-writing, editing, and perfecting each application. My mentors were immensely helpful in paring down my work, but my friends were crucial during this process. We set up “PhD Dates”  at cafes or somebody’s apartment, ordered food, and made sure we were productive.  After all, Downton Abbey and Game of Thrones repeats were a great distraction.

I applied to nine academic programs in Fall 2012, all in the Humanities. Five programs admitted me, and I accepted the University of Chicago’s Department of Near Eastern Languages and Civilizations.

Letters of Recommendation (began process in August):

I found it appropriate to ask three individuals who could speak to and emphasize three very different but important qualities about me. It is a bit daunting (and sometimes embarrassing) to approach a professor or teacher to ask for a letter of recommendation. What exactly is the best method of asking, “Professor, can you write a letter about how awesome I am?”

First, I chose the three people I thought would provide the fullest “picture” of who I am as an individual and as an academic. The initial email, which I sent in August (about four months prior to the first deadlines), requested a meeting to discuss my future and to receive advice. I prepared packets (although incomplete) with my curriculum vitae, a copy of my writing sample, a draft of my personal (academic) statement, and a list of potential programs and application due dates. These packets were prepared in the hopes that if my professor agreed to write a letter, I could immediately provide application information.

My undergraduate professor from Cal State Northridge, my language instructor from UChicago, and my Master’s thesis advisor from UChicago were the three people I approached to write letters of recommendation. Though I did not see all of the letters, I know that each wrote about my strengths from the experience they had working with me. This was vital, since three repetitive letters would have been pointless.  Every 4-6 weeks leading up to the December and January deadlines, I would email or meet them in person to discuss the progress of each application (i.e. whether they had started their letters, how I could improve my CV or statement).

 Networking (ongoing September-November):

The most important (and difficult!) part of this process was meeting every professor I mentioned in my applications.  I made it a point to visit many campuses (yes, I traveled quite a bit), and I went to many conferences with the knowledge that the professors I wanted to work with would be at those conferences.

Much like I did with my recommenders, I wrote a personalized email to each professor.  Writing personalized emails proved useful in November when two professors from different universities forwarded each other the emails I had sent them. This could have proved quite embarrassing had I sent them the same email.

In each email, I outlined my academic trajectory, but mostly focused on soliciting advice on my work.  I also asked them questions regarding their published and ongoing work.  This was the most time-consuming part of the application process, since I researched each professor and made sure they would be somebody I could work with for an extended length of time.

 Curriculum Vitae:

The easiest aspect of the application was refining my curriculum vitae. I began it as an undergraduate and continued adding to it through my Master’s program. The most troubling aspect of the CV was the order (education; presentations; publications etc). Some applications only allowed a one-page CV, so I would agonize over which sections to cut. The link to my current CV is below, and this CV is (almost) the same as the one I submitted to most doctoral programs: http://augustsamie.com/cv/

Writing Sample:

The first thing I noticed about each application was that the lengths of the writing sample varied (anything from 10 pages to 30 pages).  I had three substantial papers that I produced during the first year of my MA that I thought of using for my applications.  Each paper had strengths (and unfortunately weaknesses!). The first paper had little to do with my interests as an academic, but was (as I was told by a professor) very convincing and well written. The second paper was completely in accordance with what I proposed researching as a doctoral student, but it was, I felt, not as well researched nor as credible as the first.  The third paper, which I ultimately submitted, needed some work, but had aspects that exemplified what I am capable of doing as an academic. I spent the next two months refining it, but it already encompassed one critical aspect that the other two papers did not: my language capabilities.  I had produced this paper using secondary sources in multiple languages.

Personal Statement:

I found writing a personal statement to be impossible at first, but once I began approaching it as a puzzle, it turned into an entertaining experience.  My first draft was commented on by at least ten people, each with their own opinions on what should be added or omitted. With all the comments in hand, I proceeded to write more than six versions of my personal statement.  Since the information in my statement is private, I will not provide a draft here. The following outline is of the points made in each paragraph.

Paragraph 1:  describe how my family background led to inquiries of race and religion in Central Asia; what activities increased and informed my knowledge of my proposed area of research

Paragraph 2: discuss my arrival at the University of Chicago for my Master’s; explain briefly my thesis and theoretical approach for my MA thesis

Paragraph 3: explain how my travels through Russia and Central Asia have helped form my opinions on my research; my contacts have helped provide indispensable sources

Paragraph 4 and 5: what I am proposing to do as a doctoral student; my theoretical approaches; current scholarship on the subject and the gap my research will fill; why my research will be important

Paragraph 6: “history lesson” (remember, there are people on the acceptance committees who know nothing about your proposed area of research, so it is important to provide a brief “lesson”); after providing three of four concise sentences about your focus, tie it to your research; how and where will your research add to what we know

Paragraph 7:  discuss the professors you intend on working with at the institution (mention you have met them); explain that your language skills will help in working with sources; make clear that this institution is essential for you to continue your research because of the professors and the resources at the institution.