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Book review - Cured: How the Berlin Patients Defeated HIV and
Forever Changed Medical Science

Sunday, 25-May-2014

Why “Cured” is a useful read for biotech investors


•     It describes the science of HIV in an approachable, yet in-depth and informative way.  Beginner and

      intermediate level biotech readers will especially learn from it.

•     It includes information on the history and science behind one publicly traded biotech stock, Sangamo


•     It briefly describes how modified versions of the HIV virus are being put to other uses, and specifically

      describes Carl June’s CAR-T program in cancer.


I am pretty much an addict when it comes to reading.  Now that I have this blog up and running, I thought it would be fun to review a book or two when I come across ones that investors might find useful, especially when they touch on biotech topics.  Here is a review of an excellent book I just finished about HIV called “Cured: How the Berlin Patients Defeated HIV and Forever Changed Medical Science” by Nathalia Holt.  It is definitely worth putting on your list.


General overview


The book gives an overview of the history of the HIV and offers suggestions about how past discoveries might lead to new treatments in the future.  It tells its story through the context of two patients in Berlin, Germany who appear to have achieved functional cures through different approaches.  

One patient, who has remained anonymous, received a combination of the drugs didanosine (a reverse transcriptase inhibitor), indinaviar (a protease inhibitor), and hydroxyurea (an antineoplastic drug used in oncology) in the late 1990’s very soon after being diagnosed with HIV.  Early intervention was not universally accepted back then because HIV drug development was still in its infancy and most approaches were difficult to tolerate.  This particular patient took the above combination for about six months, went off treatment completely, and has lived with nearly undetectable levels of the virus for over 15 years.  That he was treated so early was a main reason why his investigator believed the patient achieved functional cure.


However, something many readers might not know is that recent events have intervened since the book was published and offer a new explanation.  A 2014 follow-up of this patient in the New England Journal of Medicine suggests that his cure was actually more likely due to a protective genetic factor (the HLA class I allele HLA-B*57) that makes him an elite controller.  Researchers were not aware of that back then.  While the news is certainly a bummer as far as some of the book’s theories go, I don’t think it detracts too much from the overall learning experience.  Biotech investors will still gain a lot from hearing this patient's story because it adroitly illustrates what diagnosis, treatment, and drug development were like back then.

By far the more interesting story, in my opinion, is that of the second patient, Timothy Ray Brown.  Mr. Brown was also diagnosed with HIV in the 1990’s, but his story takes a big turn a decade later when he was also diagnosed with cancer (acute myeloid leukemia).  This landed him in the care of an oncologist named Dr. Gero Hütter who wanted to try adding an experimental twist to Mr. Brown’s bone marrow transplant, a common intervention for many AML patients.


Dr. Hütter’s idea related to a protein receptor on the outside of white blood cells, called CCR5, that HIV needs to latch onto in order gain entrance to the cell and replicate.  Interestingly, about 1% of people of European descent are homozygous for a mutation in their genes (called a Δ32 mutation) that causes them to produce non-functional CCR5. Without functional CCR5, these people are naturally resistant to most strains of HIV.  With that understanding, Dr. Hütter thought it would be interesting to give Mr. Brown his bone marrow transplant from a donor who was a homozygous carrier of the mutation.  He wanted to see if the donor’s resistance to HIV would carry over to the recipient patient after the transplant.


Mr. Brown’s transplant went well.  His cancer went into remission, and his white blood cells started testing positive for the Δ32 mutation.  They also seemed to be doing a good job of controlling the HIV.  However, it was not until after a relapse of the cancer and a second transplant a year later that he was formally in the clear.  He has remained off medicine and with undetectable levels of the virus in his system ever since.  Mr. Brown’s immune system seems to have been successfully reset with this technique.


“Cured” helps you understand the science of HIV


One of the best things about the book, and something that aspiring biotech investors will especially benefit from, is how it explains the science of HIV.  Not only does it go over the basics of HIV and other retroviruses, but it also delves into more advanced topics like those genetic mutations and what causes some patients to be elite controllers.  A handful of illustrations make these topics approachable and easy to grasp.  The book also explains the science behind various methods of diagnosing the disease like ELISA and PCR testing, and OraSure’s (Nasdaq: OSUR) over-the-counter OraQuick product.  Setting aside the journeys of the two Berlin patients, the way the science is presented makes “Cured” worth reading for that alone.


A key aspect of HIV that investors will want to read up on is how the virus lays dormant in multiple organs throughout the body for years.  This partially explains why achieving outright cure has been so elusive.  Most people think of HIV as a disease of the blood, but the reality is that replication mostly happens in places like the gut and rectum, where white blood cells are densely packed.  Furthermore, once cells are infected, many of them become inactive and hide out in far reaches of the body for years.  Modern-day drugs are good at attacking HIV as it is replicating, but finding those dormant reservoirs is a much taller order.  That is one reason why patients currently need to stay on antiviral therapies forever.  Solving the problem is critical to achieving a cure one day.


The book includes information about Sangamo Biosciences


In addition to telling the history of HIV, “Cured” also describes how past discoveries might lead to new treatments.  One of the more promising approaches being researched right now is gene therapy.  A company at the forefront of that is Sangamo Biosciences (Nasdaq: SGMO), a biotech stock you have probably heard of.  Investors will enjoy how almost an entire chapter of the book is devoted to Sangamo.  It is not every day that you get to read in long form something so highly relevant to biotech investing.


Sangamo is trying to achieve a functional cure using a gene therapy technology called zinc finger nucleases (ZFNs). HIV is their most advanced program.  As the book describes in detail, ZFNs take a protein that grips DNA very tightly and combines it with an enzyme capable of cutting entire sections out of the genome.  Sangamo’s aim is to use this approach to discard the gene for the all-important CCR5 protein.  The company has already advanced the program into clinical trials in humans, and recently presented data from a phase 1/2 trial at the CROI conference in March.  You can also find some earlier work Sangamo published in New England Journal of Medicine here.


While the science of ZFNs is elegant, I personally believe Sangamo is more of an illustration of the limitations of this approach rather than a sign of coming success.  Sangamo’s technique calls for manipulating a patient’s cells outside of his or her body and then re-infusing them.  This approach has lowered viral loads initially, but the HIV always springs back.  I am guessing that is probably because such a relatively small percentage of cells are given the gene therapy.  It might be hard for them to take over in a ‘survival of the fittest’ scenario inside the body.  I have previously written that Sangamo is a stock to avoid in this market.  I’ll be cheering for them on the sidelines, but I still stand by that opinion. 


Emerging topics in biotech such as CAR-T are discussed


As further evidence that investors will enjoy the book, it also touches on what I think is THE most interesting technique emerging in oncology right now, CAR-T.  One of the investigators from the Sangamo trials is Carl June of the Perelman School of Medicine at the University of Pennsylvania.  Knowing from his experience that HIV is so adept at entering and changing the genome of white blood cells, Dr. June and his collaborators have stripped the virus down (so that it is safe) and modified it to instruct T cells to recognize CD19, a protein that is found on the outside of B cells.  By programing them to recognize and destroy B cells, this makes CAR-T an ideal approach against many types of blood cancers.


While early research must always be viewed with caution, Dr. June’s team has produced some amazing initial results.  

You probably have read about Emma Whitehead, the first patient who might have been cured from the technique.

Encouraging stories like hers have attracted investors to the space quickly.  Dr. June’s group has since licensed their program to Novartis, and other companies like Juno Therapeutics and Kite Pharma have entered the fray as well.  CAR-T has been focused on CD19 for now, but the ultimate goal is to hopefully use it against markers expressed by other cells as well.  The takeaway from the book is that things learned about HIV have made it an excellent candidate for use in immuno-oncology and other types of gene therapies.




“Cured” is an excelled book that I would recommend to almost any biotech investor.  The stories of the Berlin patients are interesting, and the book will refresh your understanding of science that is highly relevant to today’s investment themes.  It makes for a great addition to any summer reading list.


Who Am I?
Brad Loncar

I'm an individual investor from Kansas City.  My focus is on biotech stocks, but I enjoy investing in all industries. I'm an old-school, buy and hold investor who believes the best way to outperform and grow capital is to own innovative companies with good management teams over the long-term. more>>

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