Posts Tagged ‘Harvard University’

Targeting Untargetable Proto-Oncogenes

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

The following is a summary of a just published cancer research paper that describes the discovery of targetting proteins previously thought to be untargetable.

Getting Around “Undruggable” Proto-Oncogenes

Patricia Fitzpatrick Dimond, Ph.D.
The Notch1 protein and BET bromodomains are among the targets researchers are investigating. [© iQoncept – Fotolia.com]
    While multiple human cancers are associated with oncogene amplification,
  • epigenetic targets causing amplification such as transcription factors were once considered “undruggable,” or
  • unlikely to be modulated with a small molecule drug.
Generally, these proteins lack surface involutions suitable for high-affinity binding by small molecules. But by thinking outside the “loop” or the usual structures required for drug targets, investigators have been making headway in targeting the formerly untargetable.
    Multiple human cancers are associated with c-Myc gene amplification including lung carcinoma breast carcinoma, colon carcinoma, and neuroblastoma. The protogene also plays a key role in cell cycle regulation, metabolism, apoptosis, differentiation, cell adhesion, as well as in tumorigenesis, and participates in regulating hematopoietic homeostasis. Its gene product functions as a transcription regulator, part of
an extensive network of interacting factors regulating the expression, it has been estimated, of more than 15 percent of all human genes.
    While Myc oncogene family members, for example, act as key drivers in human cancers,
  • they have been considered undruggable as
  • they encode transcription factors and carry out essential functions in proliferative tissues,
  • suggesting that their inhibition could cause severe side effects.
And from a chemist’s point of view, these proteins’ surfaces are not amenable to binding drugs. In an online dialog posted on the NCI’s website in October of 2010, an investigator noted, “We don’t know how to interfere with these factors or their activities in clinical settings because, in general,
  • we lack the means to inhibit proteins that are not enzymes.”
    But by preventing key protein-protein interactions that enable the actions of these transcriptional drivers, scientists are drugging the formerly undruggable.

To Drug the Undruggable Target

    One such approach published  in Nature in 2009 by a team of Harvard scientists who was reported that they had successfully targeted a “master” protein, Notch1, which had been considered “untouchable” by conventional drugs. The protein is a
  • key transcription factor regulating genes involved in cell growth and survival but
  • like other transcription factors has proven an elusive drug target due to its structure.
The scientists said they had designed
  • a synthetic, cell-permeable alpha-helical peptide, SAHM1,
  • which could target a critical protein-protein interface in the notch transactivation complex.
The drug molecule enters cells and interferes with a protein-protein interaction essential for the transmission of cell growth signals via the Notch pathway.
    The researchers tested the drug using cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of the disease. The Notch1 gene is mutated in half of patients with T-ALL and
  • produces an inappropriately active Notch1 protein.
Activated Notch signaling has been seen in several other cancers including lung, ovarian, and pancreatic cancer, and melanoma.
    “We’ve drugged a so-called undruggable target,” said Gregory L. Verdine, Ph.D., Erving professor of chemistry at Harvard University. “This study validates the notion that you can target a transcription factor
  • by choosing a new class of molecules, namely stapled peptides.”

He added that, because the molecular logic of these proteins is similar to Notch1’s,

  • this strategy might work for other transcription factors as well.

Targeting BET

    Another emerging approach to drugging the undruggable is to target the bromo and extra C-terminal domain (BET) family of bromodomains that are
  • involved in binding epigenetic “marks” on histone proteins.
Four members of this 47-protein family interact with chromatin including histone acetylases and nucleosome remodeling complexes. Bromodomain proteins act as chromatin “readers” to recruit chromatin-regulating enzymes, including
  • “writers” and “erasers” of histone modification, to target promoters and to regulate gene expression.
As mentioned in a previous GEN article, epigenetic control systems generally involve three types of proteins:
  1. “writers”,   Writers attach chemical marks, such as methyl groups (to DNA) or acetyl groups (to the histone proteins that DNA wraps around)
  2. “readers”,  Readers bind to these marks, thereby influencing gene expression
  3. “erasers.”  Erasers remove the marks
    While investigators have considered that the precise function of the so-called BET bromodomain remains incompletely defined,
  • proteins containing this domain have become another epigenetic target for drug development companies.
  • these domains may allow researchers a way to get at oncogenic targets that were once thought undruggable including the proto-oncogene Myc.
    Small molecule inhibition of BET protein bromodomains also selectively suppresses other genes such as Bcl-2 that have important roles in cancer, as well as some NF-κB-dependent genes that have roles in both cancer and inflammation. Small molecule inhibition of BET bromodomains
  • leads to selective killing of tumor cells across a range of hematologic malignancies and in subsets of solid tumors.
In particular, the bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt’s lymphoma, human nuclear protein in testis (NUT) midline carcinoma, colon cancer, and inflammatory disease;
  • its loss is a prognostic signature for metastatic breast cancer.
    BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function, until very recently, remained unknown.
    In 2010, investigators reported in Nature that they had identified a cell-permeable small molecule that bound competitively to bromodomains, or acetyl-lysine recognition motifs. Competitive binding by the small molecule JQ1, the investigators reported,
  • displaces the BRD4 fusion oncoprotein from chromatin,
  • prompting squamous differentiation and
  • specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models.
    The authors say that these data established proof-of-concept for targeting protein–protein interactions of epigenetic readers, and could provide a versatile
  • chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
    More recently, writing in the Journal of Medicinal Chemistry, investigators at GlaxoSmithKline reported that they had successfully optimized
a class of benzodiazepines as BET bromodomain inhibitors, apparently without any prior knowledge of identified molecular targets.
Significant medicinal chemistry provided the bromodomain inhibitor, I-BET762 or GSK525762, which is currently in a Phase I clinical trial for the treatment of NUT midline carcinoma, a rare but lethal form of cancer, and other cancers.

 Casting a Wide Net

    Constellation Pharmaceuticals of Cambridge, MA, announced that it has initiated a Phase I clinical trial of CPI-0610, a novel small molecule BET protein bromodomain inhibitor, in patients with previously treated and progressive lymphomas. This first-in-human trial is currently open at Sarah Cannon Research Institute in Nashville, Tennessee, and at the John Theurer Cancer Center in Hackensack, New Jersey. Additional study sites in the U.S. will join the trial over the next several months. Studies of CPI-0610 are also planned in patients with multiple myeloma and in patients with acute leukemia or myelodysplastic syndrome.
    Constellation’s CMO, Michael Cooper, M.D. told GEN that “small molecule inhibitors of BET protein bromodomains have demonstrated broad activity against hematologic malignancies in preclinical models. And this activity can be achieved in vivo with levels of compound exposure that are well tolerated. While we are encouraged by these observations, what really makes the area interesting is
  • the novel mechanism by which BET protein bromodomain inhibitors elicit their biologic effects.
  • They disrupt the interaction of BET proteins with acetylated lysine residues on histones and thereby
  • suppress the transcription of key cancer-related genes such as MYC, BCL-2, and a subset of NF-κB-dependent genes.
These genes have in the past been difficult to target with small molecules. In light of the breadth of the activity in preclinical models of hematologic malignancies and the important genes that are targeted, we intend to cast a wide net across hematologic malignancies in the clinic.”
    Robert Sims, Ph.D., and senior director of biology at Constellation explained that BET protein bromodomain inhibition is only of several areas of interest for the company. “The BET proteins constitute one class of epigenetic targets, namely
  • molecules that recognize patterns in chromatin architecture and
  • either enhance or suppress gene transcription.
Constellation’s approach to epigenetics also includes programs in the enzymes that modify the architecture of chromatin, for example by the
  • methylation or demethylation of histone proteins (writers and erasers, respectively).
Even though our first drug candidate is directed against a set of reader proteins, we are also looking at inhibitors of the writer protein, EZH2, which is mutated in some types of non-Hodgkin lymphoma and overexpressed in many malignancies.”
    In January 2012, Constellation and Genentech announced collaboration based on the science of epigenetics and chromatin biology to discover and develop innovative treatments for cancer and other diseases. Each company will each commit a significant portion of their research and development efforts to the advancement of programs under the collaboration, and each party will have the right to retain exclusive rights to programs emerging from the collaboration.
    And more biotech giants can be expected to enter the field of epigenetics as smaller companies advance into the clinic with this novel approach to controlling gene expression gone wrong in cancer cells.
Patricia Fitzpatrick Dimond, Ph.D. (pdimond@genengnews.com), is technical editor at Genetic Engineering & Biotechnology News
Employing Metabolomics in Cell Culture and Bioprocessing: Gaining greater predictability, control and quality
Challenges in developing and producing biotherapeutics are numerous and dynamic, including various market drivers and industry responses. Finding effective measures to support a foundation of control, predictability, and quality have been a concern and have paved the way to seeking out and applying newer technologies such as metabolomics successfully to bioprocessing. This webinar will first navigate through the landscape and challenges in developing and producing biotherapeutics. The journey continues with a walk through of the rationale for why metabolomics is a key tool for addressing critical bioprocessing needs followed by specific case studies and examples of how a functional metabolomic approach has been applied.
There are many relevant applications for functional metabolomics in bioprocessing starting with process development that include being able to: boost titer or productivity, improve product quality, enhance viability, or optimize defined media. The technology has be employed in biomarker discovery applications for the following purposes: to identify predictors of lactate consumption, to assess product quality, to predict indicative biomarkers of bioreactor performance or identify ideal clones. Lastly, functional metabolomics has been applied to enrich DOE experiments and troubleshooting for: historical deviation, process transfer, scale-up issues, disposable concerns, and lot or performance changes.

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Reporter: Aviva Lev-Ari, PhD, RN

J R Soc Interface. 2013 Feb 20;10(82):20130006. doi: 10.1098/rsif.2013.0006. Print 2013 May 6.

The inverse association of cancer and Alzheimer’s: a bioenergetic mechanism.

Demetrius LASimon DK.


Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA. ldemetr@oeb.harvard.edu

Screen Shot 2021-07-19 at 7.09.12 PM

Word Cloud By Danielle Smolyar


The sporadic forms of cancer and Alzheimer’s disease (AD) are both age-related metabolic disorders. However, the molecular mechanisms underlying the two diseases are distinct: cancer is described by essentially limitless replicative potential, whereas neuronal death is a key feature of AD. Studies of the origin of both diseases indicate that their sporadic forms are the result of metabolic dysregulation, and a compensatory increase in energy transduction that is inversely related. In cancer, the compensatory metabolic effect is the upregulation of glycolysis-the Warburg effect; in AD, a bioenergetic model based on the interaction between astrocytes and neurons indicates that the compensatory metabolic alteration is the upregulation of oxidative phosphorylation-an inverse Warburg effect. These two modes of metabolic alteration could contribute to an inverse relation between the incidence of the two diseases. We invoke this bioenergetic mechanism to furnish a molecular basis for an epidemiological observation, namely the incidence of sporadic forms of cancer and AD is inversely related. We furthermore exploit the molecular mechanisms underlying the diseases to propose common therapeutic strategies for cancer and AD based on metabolic intervention.

PMID: 23427097
PMCID: PMC3627084
 [Available on 2014/5/6]

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The Promise of Personalized Medicine

Reporter: Larry H Bernstein, MD, FCAP


 Realizing the Promise of Personalized Medicine

Harvard Business Review
MG Aspinal, RG Hamermesh
Obsolete business models, regulations, reimbursement systems, and physicians stand in the way

NewYear for Angels

NewYear for Angels (Photo credit: Wikipedia)


BusinessModel (Photo credit: Wikipedia)


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Curator: Aviva Lev-Ari, PhD, RN

Chaperon Protein Mechanism inspired MIT Team to Model the Role of Genetic Mutations on Cancer Progression, proposing the next generation of Oncology drugs to aim at Suppression of Passenger Mutations. Current drug, in clinical trials, use the Chaperon Protein Mechanism to suppress Driver Mutations.

Deleterious Mutations in Cancer Progression

Kirill S. Korolev1, Christopher McFarland2, and Leonid A. Mirny3

1Department of Physics, MIT, Cambridge, MA.

E-mail: papers.korolev@gmail.com

2Graduate Program in Biophysics, Harvard University, Cambridge, MA.

3Health Sciences and Technology, MIT, Cambridge, MA

The research was funded by the National Institutes of Health/National Cancer Institute Physical Sciences Oncology Center at MIT.



Deleterious passenger mutations significantly affect evolutionary dynamics of cancer. Including passenger mutations in evolutionary models is necessary to understand the role of genetic diversity in cancer progression and to create new treatments based on the accumulation of deleterious passenger mutations.

Evolutionary models of cancer almost exclusively focus on the acquisition of driver mutations, which are beneficial to cancer cells. The driver mutations, however, are only a small fraction of the mutations found in tumors. The other mutations, called passenger mutations, are typically neglected because their effect on fitness is assumed to be very small. Recently, it has been suggested that some passenger mutations are slightly deleterious. We find that deleterious passengers significantly affect cancer progression. In particular, they lead to a critical tumor size, below which tumors shrink on average, and to an optimal mutation rate for cancer evolution.

ANCER is an outcome of somatic evolution [1-3]. To outcompete their benign sisters, cancer cells need to acquire many heritable changes (driver mutations) that enable proliferation. In addition to the rare beneficial drivers, cancer cells must also acquire neutral or slightly deleterious passenger mutations [4]. Indeed, the number of possible passengers exceeds the number of possible drivers by orders of magnitude. Surprisingly, the effect of passenger mutations on cancer progression has not been explored. To address this problem, we developed an evolutionary model of cancer progression, which includes both drivers and passengers. This model was analyzed both numerically and analytically to understand how mutation rate, population size, and fitness effects of mutations affect cancer progression.


Upon including passengers in our model, we found that cancer is no longer a straightforward progression to malignancy. In particular, there is a critical population size such that smaller populations accumulate passengers and decline, while larger populations accumulate drivers and grow. The transition to cancer for small initial populations is, therefore, stochastic in nature and is similar to diffusion over an energy barrier in chemical kinetics. We also found that there is an optimal mutation rate for cancer development, and passengers with intermediate fitness costs are most detrimental to cancer. The existence of an optimal mutation rate could explain recent clinical data [5] and is in stark contrast to the predictions of the models neglecting passengers. We also show that our theory is consistent with recent sequencing data.



Just as some mutations in the genome of cancer cells actively spur tumor growth, it would appear there are also some that do the reverse, and act to slow it down or even stop it, according to a new US study led by MIT.

Senior author, Leonid Mirny, an associate professor of physics and health sciences and technology at MIT, and colleagues, write about this surprise finding in a paper to be published online this week in the Proceedings of the National Academy of Sciences.

In a statement released on Monday, Mirny tells the press:

“Cancer may not be a sequence of inevitable accumulation of driver events, but may be actually a delicate balance between drivers and passengers.”

“Spontaneous remissions or remissions triggered by drugs may actually be mediated by the load of deleterious passenger mutations,” he suggests.

Cancer Cell‘s Genome Has “Drivers” and “Passengers”

Your average cancer cell has a genome littered with thousands of mutations and hundreds of mutated genes. But only a handful of these mutated genes are drivers that are responsible for the uncontrolled growth that leads to tumors.

Up until this study, cancer researchers have mostly not paid much attention to the “passenger” mutations, believing that because they were not “drivers”, they had little effect on cancer progression. 

Now Mirny and colleagues have discovered, to their surprise, that the “passengers” aren’t there just for the ride. In sufficient numbers, they can slow down, and even stop, the cancer cells from growing and replicating as tumors. 

New Drugs Could Target the Passenger Mutations in Protein Chaperoning

Although there are already several drugs in development that target the effect of chaperone proteins in cancer, they are aiming to suppress driver mutations.

Recently, biochemists at the University of Massachusetts Amherst“trapped” a chaperone in action, providing a dynamic snapshot of its mechanism as a way to help development of new drugs that target drivers.

But Mirny and colleagues say there is now another option: developing drugs that target the same chaperoning process, but their aim would be to encourage the suppressive effect of the passenger mutations.

They are now comparing cells with identical driver mutations but different passenger mutations, to see which have the strongest effect on growth.

They are also inserting the cells into mice to see which are the most likely to lead to secondary tumors (metastasize).

Written by Catharine Paddock PhD
Copyright: Medical News Today



After proteins are synthesized, they need to be folded into the correct shape, and chaperones help with that process. In cancerous cells, chaperones help proteins fold into the correct shape even when they are mutated, helping to suppress the effects of deleterious mutations.
Several potential drugs that inhibit chaperone proteins are now in clinical trials to treat cancer, although researchers had believed that they acted by suppressing the effects of driver mutations, not by enhancing the effects of passengers.

In current studies, the researchers are comparing cancer cell lines that have identical driver mutations but a different load of passenger mutations, to see which grow faster. They are also injecting the cancer cell lines into mice to see which are likeliest to metastasize.

Drugs that tip the balance in favor of the passenger mutations could offer a new way to treat cancer, the researchers say, beating it with its own weapon — mutations. Although the influence of a single passenger mutation is minuscule, “collectively they can have a profound effect,” Mirny says. “If a drug can make them a little bit more deleterious, it’s still a tiny effect for each passenger, but collectively this can build up.”

In natural populations, selection weeds out deleterious mutations. However, Mirny and his colleagues suspected that the evolutionary process in cancer can proceed differently, allowing mutations with only a slightly harmful effect to accumulate.

If enough deleterious passengers are present, their cumulative effects can slow tumor growth, the simulations found. Tumors may become dormant, or even regress, but growth can start up again if new driver mutations are acquired. This matches the cancer growth patterns often seen in human patients.

“Spontaneous remissions or remissions triggered by drugs may actually be mediated by the load of deleterious passenger mutations.”

When they analyzed passenger mutations found in genomic data taken from cancer patients, the researchers found the same pattern predicted by their model — accumulation of large quantities of slightly deleterious mutations.


Massachusetts Institute of Technology (2013, February 4). Some cancer mutations slow tumor growth. ScienceDaily. Retrieved February 4, 2013, from http://www.sciencedaily.com­/releases/2013/02/130204154011.htm

Biochemists Trap A Chaperone Machine In Action

Main Category: Biology / Biochemistry
Article Date: 11 Dec 2012 – 0:00 PST

Molecular chaperones have emerged as exciting new potential drug targets, because scientists want to learn how to stop cancer cells, for example, from using chaperones to enable their uncontrolled growth. Now a team of biochemists at the University of Massachusetts Amherst led by Lila Gierasch have deciphered key steps in the mechanism of the Hsp70 molecular machine by “trapping” this chaperone in action, providing a dynamic snapshot of its mechanism.

She and colleagues describe this work in the current issue of Cell. Gierasch’s research on Hsp70 chaperones is supported by a long-running grant to her lab from NIH’s National Institute for General Medical Sciences.

Molecular chaperones like the Hsp70s facilitate the origami-like folding of proteins, made in the cell’s nanofactories or ribosomes, from where they emerge unstructured like noodles. Proteins only function when folded into their proper structures, but the process is so difficult under cellular conditions that molecular chaperone helpers are needed. 

The newly discovered information about chaperone action is important because all rapidly dividing cells use a lot of Hsp70, Gierasch points out. “The saying is that cancer cells are addicted to Hsp70 because they rely on this chaperone for explosive new cell growth. Cancer shifts our body’s production of Hsp70 into high gear. If we can figure out a way to take that away from cancer cells, maybe we can stop the out-of-control tumor growth. To find a molecular way to inhibit Hsp70, you’ve got to know how it works and what it needs to function, so you can identify its vulnerabilities.”

Chaperone proteins in cells, from bacteria to humans, act like midwives or bodyguards, protecting newborn proteins from misfolding and existing proteins against loss of structure caused by stress such as heat or a fever. In fact, the heat shock protein (Hsp) group includes a variety of chaperones active in both these situations.

As Gierasch explains, “New proteins emerge into a challenging environment. It’s very crowded in the cell and it would be easy for them to get their sticky amino acid chains tangled and clumped together. Chaperones bind to them and help to avoid this aggregation, which is implicated in many pathologies such as neurodegenerative diseases. This role of chaperones has also heightened interest in using them therapeutically.”

However, chaperones must not bind too tightly or a protein can’t move on to do its job. To avoid this, chaperones rapidly cycle between tight and loose binding states, determined by whether ATP or ADP is bound. In the loose state, a protein client is free to fold or to be picked up by another chaperone that will help it fold to do its cellular work. In effect, Gierasch says, Hsp70s create a “holding pattern” to keep the protein substrate viable and ready for use, but also protected.

She and colleagues knew the Hsp70’s structure in both tight and loose binding affinity states, but not what happened between, which is essential to understanding the mechanism of chaperone action. Using the analogy of a high jump, they had a snapshot of the takeoff and landing, but not the top of the jump. “Knowing the end points doesn’t tell us how it works. There is a shape change in there that we wanted to see,” Gierasch says.

To address this, she and her colleagues postdoctoral fellows Anastasia Zhuravleva and Eugenia Clerico obtained “fingerprints” of the structure of Hsp70 in different states by using state-of-the-art nuclear magnetic resonance (NMR) methods that allowed them to map how chemical environments of individual amino acids of the protein change in different sample conditions. Working with an Hsp70 known as DnaK from E. coli bacteria, Zhuravleva and Clerico assigned its NMR spectra. In other words, they determined which peaks came from which amino acids in this large molecule.

The UMass Amherst team then mutated the Hsp70 so that cycling between tight and loose binding states stopped. As Gierasch explains, “Anastasia and Eugenia were able to stop the cycle part-way through the high jump, so to speak, and obtain the molecular fingerprint of a transient intermediate.” She calls this accomplishment “brilliant.”

Now that the researchers have a picture of this critical allosteric state, that is, one in which events at one site control events in another, Gierasch says many insights emerge. For example, it appears nature uses this energetically tense state to “tune” alternate versions of Hsp70 to perform different cellular functions. “Tuning means there may be evolutionary changes that let the chaperone work with its partners optimally,” she notes.

“And if you want to make a drug that controls the amount of Hsp70 available to a cell, our work points the way toward figuring out how to tickle the molecule so you can control its shape and its ability to bind to its client. We’re not done, but we made a big leap,” Gierasch adds. “We now have a idea of what the Hsp70 structure is when it is doing its job, which is extraordinarily important.” 

Article adapted by Medical News Today from original press release. Click ‘references’ tab above for source.
Visit our biology / biochemistry section for the latest news on this subject.


[1] Michor F, Iwasa Y, and Nowak MA (2004) Dynamics of cancer

progression. Nature Reviews Cancer 4, 197-205.

[2] Crespi B and Summers K (2005) Evolutionary biology of cancer.

Trends in Ecology and Evolution 20, 545-552.

[3] Merlo LMF, et al. (2006) Cancer as an evolutionary and ecological

process. Nature Reviews Cancer 6, 924-935.

[4] McFarland C, et al. “Accumulation of deleterious passenger mutations

in cancer,” in preparation.

[5] Birkbak NJ, et al. (2011) Paradoxical relationship between

chromosomal instability and survival outcome in cancer. Cancer

Research 71,3447-3452.

Other related articles on this Open Access Online Scientific Journal include the following:

Hold on. Mutations in Cancer do good.


Rational Design of Allosteric Inhibitors and Activators Using the Population-Shift Model: In Vitro Validation and Application to an Artificial Biosensor


LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2


Exome sequencing of serous endometrial tumors shows recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes


Genome-Wide Detection of Single-Nucleotide and Copy-Number Variation of a Single Human Cell(1)


Gastric Cancer: Whole-genome reconstruction and mutational signatures


Pregnancy with a Leptin-Receptor Mutation


Mitochondrial mutation analysis might be “1-step” away


Genome-wide Single-Cell Analysis of Recombination Activity and De Novo Mutation Rates in Human Sperm


A Prion Like-Protein, Protein Kinase Mzeta and Memory Maintenance


Hope for Male Contraception: A small molecule that inhibits a protein important for chromatin organization can cause reversible sterility in male mice


Protein Folding may lead to better FLU Vaccine


SNAP: Predict Effect of Non-synonymous Polymorphisms: How well Genome Interpretation Tools could Translate to the Clinic


Drugging the Epigenome


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Reporter: Prabodh Kandala, PhD

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Word Cloud By Danielle Smolyar

A typical cancer cell has thousands of mutations scattered throughout its genome and hundreds of mutated genes. However, only a handful of those genes, known as drivers, are responsible for cancerous traits such as uncontrolled growth. Cancer biologists have largely ignored the other mutations, believing they had little or no impact on cancer progression.

But a new study from MIT, Harvard University, the Broad Institute and Brigham and Women’s Hospital reveals, for the first time, that these so-called passenger mutations are not just along for the ride. When enough of them accumulate, they can slow or even halt tumor growth.

The findings, reported in this week’sProceedings of the National Academy of Sciences, suggest that cancer should be viewed as an evolutionary process whose course is determined by a delicate balance between driver-propelled growth and the gradual buildup of passenger mutations that are damaging to cancer, says Leonid Mirny, an associate professor of physics and health sciences and technology at MIT and senior author of the paper.

Furthermore, drugs that tip the balance in favor of the passenger mutations could offer a new way to treat cancer, the researchers say, beating it with its own weapon — mutations. Although the influence of a single passenger mutation is minuscule, “collectively they can have a profound effect,” Mirny says. “If a drug can make them a little bit more deleterious, it’s still a tiny effect for each passenger, but collectively this can build up.”

Lead author of the paper is Christopher McFarland, a graduate student at Harvard. Other authors are Kirill Korolev, a Pappalardo postdoctoral fellow at MIT, Gregory Kryukov, a senior computational biologist at the Broad Institute, and Shamil Sunyaev, an associate professor at Brigham and Women’s.

Power struggle

Cancer can take years or even decades to develop, as cells gradually accumulate the necessary driver mutations. Those mutations usually stimulate oncogenes such as Ras, which promotes cell growth, or turn off tumor-suppressing genes such as p53, which normally restrains growth.

Passenger mutations that arise randomly alongside drivers were believed to be fairly benign: In natural populations, selection weeds out deleterious mutations. However, Mirny and his colleagues suspected that the evolutionary process in cancer can proceed differently, allowing mutations with only a slightly harmful effect to accumulate.

To test this theory, the researchers created a computer model that simulates cancer growth as an evolutionary process during which a cell acquires random mutations. These simulations followed millions of cells: every cell division, mutation and cell death.

They found that during the long periods between acquisition of driver mutations, many passenger mutations arose. When one of the cancerous cells gains a new driver mutation, that cell and its progeny take over the entire population, bringing along all of the original cell’s baggage of passenger mutations. “Those mutations otherwise would never spread in the population,” Mirny says. “They essentially hitchhike on the driver.”

This process repeats five to 10 times during cancer development; each time, a new wave of damaging passengers is accumulated. If enough deleterious passengers are present, their cumulative effects can slow tumor growth, the simulations found. Tumors may become dormant, or even regress, but growth can start up again if new driver mutations are acquired. This matches the cancer growth patterns often seen in human patients.

“Cancer may not be a sequence of inevitable accumulation of driver events, but may be actually a delicate balance between drivers and passengers,” Mirny says. “Spontaneous remissions or remissions triggered by drugs may actually be mediated by the load of deleterious passenger mutations.”

When they analyzed passenger mutations found in genomic data taken from cancer patients, the researchers found the same pattern predicted by their model — accumulation of large quantities of slightly deleterious mutations.

Tipping the balance

In computer simulations, the researchers tested the possibility of treating tumors by boosting the impact of deleterious mutations. In their original simulation, each deleterious passenger mutation reduced the cell’s fitness by about 0.1 percent. When that was increased to 0.3 percent, tumors shrank under the load of their own mutations.

The same effect could be achieved in real tumors with drugs that interfere with proteins known as chaperones, Mirny suggests. After proteins are synthesized, they need to be folded into the correct shape, and chaperones help with that process. In cancerous cells, chaperones help proteins fold into the correct shape even when they are mutated, helping to suppress the effects of deleterious mutations.

Several potential drugs that inhibit chaperone proteins are now in clinical trials to treat cancer, although researchers had believed that they acted by suppressing the effects of driver mutations, not by enhancing the effects of passengers.

In current studies, the researchers are comparing cancer cell lines that have identical driver mutations but a different load of passenger mutations, to see which grow faster. They are also injecting the cancer cell lines into mice to see which are likeliest to metastasize.


Massachusetts Institute of Technology (2013, February 4). Some cancer mutations slow tumor growth. ScienceDaily. Retrieved February 4, 2013, from http://www.sciencedaily.com­/releases/2013/02/130204154011.htm

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Reporter: Aviva Lev-Ari, PhD, RN


Spotted on

Exclusive: How US and UK Physicians’ Ethics Differ

Harris Meyer

Nov 20, 2012



US and UK physicians receive medical training so similar that they can readily practice in either the United States or the United Kingdom. They share a common history and culture and speak the same language, more or less.

There were notable contrasts on attitudes toward what doctors regard as

  • futile care,
  • maintaining patient confidentiality in certain situations,
  • alerting patients about poor-quality physicians, and
  • telling patients the truth about terminal conditions.
  • Their biggest difference seen was about whether to defer to the treatment wishes of patients’ families (Table).

But a newMedscape survey of nearly 25,000 US and UK physicians found that doctors in the 2 nations hold markedly different views on some thorny medical ethics issues.

Table. Differences in Attitudes Between US and UK Physicians, Medscape 2012 Ethics Report

Question US Physicians UK Physicians
Would you ever go against a family’s wishes to end treatment and continue treating a patient whom you felt had a chance to recover? Yes: 23% Yes: 57%
Is it ever acceptable to perform “unnecessary” procedures due to malpractice concerns? Yes: 23% Yes: 9%
Is it right to provide intensive care to a newborn who either will die soon or survive with an objectively terrible quality of life? Yes: 34% Yes: 22%
Would you ever hide information from a patient about a terminal or pre-terminal diagnosis if you believed it would help bolster the patient’s spirit? Yes: 10% Yes: 14%
Would you give life-sustaining therapy if you believed it to be futile? Yes: 35% Yes: 22%
Should physician-assisted suicides be allowed in some situations? Yes: 47% Yes: 37%
Would you inform a patient if he or she were scheduled to have a procedure done by a physician whose skill you knew to be substandard? Yes: 47% Yes: 32%
Is it acceptable to breach patient confidentiality if a patient’s health status could harm others? Yes: 63% Yes: 74%
Would you ever decide to devote scarce or costly resources to a younger patient rather than to one who was older but not facing imminent death? Yes: 27% Yes: 24%

© Medscape 2012

Several factors contribute to the differences: different views toward patient-centeredness; different medical liability climate; the way physicians are paid; national religious attitudes; and the nature of the relationship between physicians, patients, and patients’ families.

The survey was conducted as part of Medscape’s Physician Ethics Report 2012. Survey questionnaires were sent to physicians in a wide range of medical specialties in each country. Completed questionnaires were received from more than 24,000 US physicians and 940 UK physicians. The statistical significance of the differences in responses between US and UK doctors was not calculated.

One obvious difference that could affect attitudes is that most US physicians work either independently or for private hospital and medical groups and receive fee-for-service payment, while most UK physicians work directly or indirectly for the country’s socialized National Health Service (NHS). In Great Britain, most medical specialists work as salaried staff in publicly operated hospitals, while most primary care physicians work independently and receive a mix of fee-for-service payments, per-patient global payments, and salary.

“The big difference is the way the system is funded and the culture of the United Kingdom,” says Brian Jarman, MD, a medical professor at Imperial College in London who serves on the NHS’s advisory committee on resource allocation. “I don’t think our decisions are as affected by financial considerations as in the US.”

Another major distinction: There’s less medical malpractice litigation in the UK. On top of that, UK medical specialists receive liability coverage through their hospital, while general practitioners have their premiums offset by NHS payments. In the US, physicians worry a lot more about malpractice suits, and doctors in independent practice are responsible for paying sizable liability premiums on their own.

The largest percentage difference in the survey — and one of the most provocative findings — was seen on the question of whether the doctor would ever go against a family’s wishes to end treatment and continue treating a patient who the doctor felt had a chance to recover. Most UK physicians in the survey — 57% — said yes, compared with just 23% of US physicians. That finding cut against the view that UK doctors are more likely to ration, and it also highlighted an important cultural gap.

“In most places in the world, doctors think they know the right treatment and do it,” says Dr. Lachlan Forrow, MD, a Harvard University medical ethicist and palliative care specialist. “My German friends say patients and families expect doctors to make decisions. In the US we might defer more to the patient and family.”

On top of that, he adds, families in the US probably express their wishes with more vehemence than in the UK and are more likely to file a lawsuit if the doctor goes against their wishes.

Differences Were Surprising

But differing attitudes and responses to survey questions didn’t always fall along lines predictable by economics.

It’s often thought that UK doctors are more cost-conscious and more apt to ration services than US doctors are, given that US doctors are paid more for providing more procedures and services, while UK doctors work in a budgeted, socialized medicine environment. The responses to the survey, however, suggest that this is true in some situations and not true in others.

Even so, the experts found more similarities than differences in the responses, with large percentages of doctors from both countries responding to many of these tough ethical questions by choosing “it depends.” Indeed, the responses of US and UK doctors were comparable on most of the questions, including informing patients about medical errors, reporting impaired colleagues, performing abortions regardless of personal beliefs, and notifying patients about risks of a procedure when obtaining informed consent.

“One of the findings is how remarkably small the differences are,” says Don Berwick, MD, a pediatrics and health policy professor at Harvard University and former head of the Centers for Medicare & Medicaid Services who has done extensive quality-improvement consulting work with the UK’s NHS.

For a majority of issues, US and UK physicians are generally in agreement. For example, on the question of whether it’s right to provide intensive care to a newborn who either will die soon or survive with poor quality of life, US physicians were more likely than UK physicians to say yes — 34% to 22% . But the largest group in both countries — about 40% — said that it depends.

Dr. Forrow says this finding shows that doctors in both countries properly base decisions on individual circumstances. “What if grandma wants to see the baby before she dies and the baby won’t suffer? So it does depend.”

Candor With Patients

Another intriguing difference came on the question of whether the doctor would hide information from a patient about a terminal or pre-terminal diagnosis if the doctor believed it would help the patient’s spirit. Far more US than UK doctors – 72% vs 54% — said, “No, I am always completely truthful about diagnoses,” while more UK than US doctors — 33% vs 18% — said that it depends.

Dr. Berwick says this difference may result from a stronger sense of customer focus in the US. “Patient-centeredness as a fundamental property is better developed in the US than in the UK,” he says. “US doctors say it’s the patient’s right to know, while British doctors might say, ‘In my judgment it would be better for patients for me to not always be completely truthful.'”

Doctors in the 2 countries also differed on the question of whether they would ever give life-sustaining therapy that they believed to be futile, with 35% of US doctors and just 22% of UK doctors saying yes. About 40% of both groups said that it depends.

“The implication is that there is a financial incentive in the US to maintain the end-of-life patient in the hospital, and that incentive is not there in the UK,” Dr. Jarman says.

Societal and Religious Differences

Similarly, US and UK doctors differed on the question of whether it’s right to provide intensive care to a newborn who either will die soon or survive with poor quality of life, with US physicians more likely to say yes.

Both Dr. Forrow and Dr. Jarman agreed that there likely are societal religious factors influencing these differences over whether to provide what could be called futile care.

“The US is a more religious society,” Dr. Forrow says. “We do all kinds of things that are not medically necessary but the patient thinks they are necessary. When doctors think something is futile, patients and families object more. They say, ‘Give God a chance.'”

In contrast, Dr. Jarman says, “The UK is not a religious country and people don’t go to church as much, so those considerations wouldn’t be there.”

Despite greater religiosity in the US, American doctors were somewhat more likely than UK doctors to say that physician-assisted suicide should be allowed in some situations — 47% to 37%. That could be related to the fact that physician-assisted death for terminally ill patients is legal in 3 US states but remains illegal in the UK.

Protecting Other Physicians?

US doctors also were more likely than UK doctors to say that they would inform a patient if they felt a doctor scheduled to perform a procedure on the patient had substandard skill levels — 47% to 32%. Nearly 40% in both countries said that it depends.

“British doctors are more protective of their colleagues than US doctors are,” Dr. Berwick says. “This implies that US doctors are getting a little more comfortable about transparency on clinical performance.”

Dr. Jarman said that this difference in attitude could be a holdover from his country’s old General Medical Council rule, abolished in the 1980s, under which a doctor who reported a colleague for doing something wrong risked being barred from practice.

Finally, the survey showed a difference in attitude toward patient confidentiality and reporting communicable diseases. UK doctors were more likely than US doctors to say that it’s acceptable to breach patient confidentiality if a patient’s health status could harm others — 74% to 63%.

Dr. Berwick explained that by saying that more UK doctors than US doctors receive public training that encourages reporting of communicable diseases, and that the US has a very strong patient confidentiality and privacy law.

Dr. Jarman noted that the General Medical Council rules encourage physicians to break confidentiality and report patients’ communicable diseases or other conditions posing harm or risk to others. “If someone is causing harm to others, doctors are correct in breaking confidentiality for the good of the state,” he says.

Dr. Berwick says that the results of the Medscape survey are complex, revealing some important differences between US and UK physicians. But overall he feels reassured by their shared ethical values.

“A significant portion in both countries say that they will make decisions based on the details of the case,” he says. “They are willing to consider treatment efficacy. They are sensitive to the social world of the patient and what the families are feeling. They are connecting in the most humane way to the patient’s entire circumstance.”

Dr. Jarman says he found the survey interesting and challenging. “You know the correct answers but you also know that with certain patients you’ve got to be human and not totally follow the rules,” he says. “You have to be a little bit human about it.”






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Reporter: Aviva Lev-Ari, PhD, RN

Personal Tale of JL’s Whole Genome Sequencing

Word Cloud by Daniel Menzin

Unexpected scary findings: the tale of John Lauerman’s whole genome sequencing

FEBRUARY 15, 2012
Joe Thakuria draws John Lauerman's blood
Joe Thakuria draws John Lauerman’s blood for whole genome sequencing. By Madeleine Price Ball, licensed under CC-BY-SA.

Madeleine Price Ball, PhD is a PGP research scientist in George Church’s lab at Harvard Medical School.

Several months ago John Lauerman, a reporter for Bloomberg News, approached the Personal Genome Project interested in having his whole genome sequenced. While we have hundreds of genomes in the sequencing pipeline, of the dozen or so genomes we have sequenced to-date, so far the results have been for the most part uneventful.

Lauerman’s case was different: we found something rare and “famous”, and something that nobody could have anticipated by looking through family history: a mutation that was acquired rather than inherited. This genetic variant (JAK2-V617F) is one of a number of mutations that can accumulate in blood stem cells, a precursor that could lead to several rare blood diseases.

Last night Lauerman published his experience, and we encourage all participants to read it. It confronts us with a scenario that seems likely to affect others who forge into this new and unknown territory: the very real possibility that whole genome sequencing may uncover something unexpected, ambiguous, and scary. This certainly isn’t an outcome we anticipate for most participants, but it is a rare possibility all should be aware of. Would you rather know that you carry such a variant, even if that knowledge might not help your health at all? Although some would decline, PGP participants are the sort of people who say: “Yes, I’ll take that risk, I’d rather know!” [see footnote]

His experience also illustrates potential for the Personal Genome Project to guide health care, for himself and for those who follow. The JAK2-V617F variant is so rarely seen in healthy individuals, we have very little understanding of what to expect. It has almost always been seen after a patient is diagnosed with a disease, not before. Will he develop one of these diseases? If so, which one? Perhaps many people carry the variant but never develop any symptoms of disease. In coming years Lauerman will likely continue to monitor his blood for signs of disease. It is possible that he will never develop the disease, and we hope this is the case. On the other hand, through monitoring he may detect disease sooner than he otherwise would have. By making his experiences public, his case can inform future individuals who confront the same finding.

As we move onward to sequencing hundreds and thousands of genomes, we can’t promise such interpretations will be made in a timely manner. We’re working with other groups to improve our ability to interpret genomes — and PGP participants are the perfect testbed for this development! — but it’s much harder than you might think. Genome data is made public in 30 days, but months or even years could pass before a serious and potentially scary variant is noticed. Participating in the PGP not only means that you risk learning ambiguous and scary news, but that it may be uncovered long after your data has been made public. We are always grateful to participants who choose to step into that unknown territory of genome sequencing, and who share their data so that others may learn.

Footnote: In the early stages of enrollment, individuals interested in joining the Personal Genome Project are asked to think about whether there are specific types of genetic information that they might not want to learn about themselves. Our examples include medical conditions with no effective cures or therapies, cancer, degenerative diseases, and stigmatized traits (e.g. mental illness). We do not offer the review or redacting of such information on a case-by-case basis. Only participants who wish to take the risk of learning such information are allowed to proceed with enrollment.




Harvard Mapping My DNA Turns Scary as Threatening Gene Emerges

By John Lauerman – Feb 15, 2012 12:01 AM ET

Four months after I walked into a lab at Harvard University and gave a vial of blood to have my genome sequenced, my search to understand my DNA led me to Mark Sanders, a former Indiana firefighter.

It took a little while to explain why I was calling and then he told me his story:

Sophie Liu, research scientist at Complete Genomics Inc., at a sequencing center at the company’s research facility in Mountain View, California. Photographer: David Paul Morris/Bloomberg

Feb. 15 (Bloomberg) — Bloomberg News reporter John Lauerman talks about the results of his genome sequencing. The genome contains the DNA instructions for making all the body’s cells and tissues. Lauerman discussed the report with a team from Harvard Medical School’s Personal Genome Project, who will use the results in their efforts to better understand variations in the human genome and their implications for health and disease. (Source: Bloomberg)

Joseph Thakuria, clinical director of the Personal Genome Project draws blood from Bloomberg reporter John Lauerman for the Project at Harvard Medical School in Boston on Sept. 13, 2011. Photographer: Madeleine Price Ball/Harvard Medical School via Bloomberg

Deep Breath

After recovering, Sanders retired from firefighting to garden and play the fiddle. He knows other myelofibrosis patients who haven’t fared as well.

“I had been so physically fit all my life,” he said. “There’s no reason or rhyme to why I have it or got it, and there’s not a lot of people around you can talk to who have it.”

I hung up the phone and took a deep breath. DNA in his blood cells carried the same rare genetic variant that my sequencing had revealed.

The variant is linked to a group of blood disorders, of which primary myelofibrosis is the most serious. Doctors don’t know whether this gene variant itself causes disease, yet it is seen so often in three blood disorders that its presence is used to confirm their diagnosis. I had to consider that my future might hold a fate similar to Sanders’s.

Genome-Sequencing Report

My path to Sanders began on Monday, Jan. 2, when I was sitting alone in my office in downtown Boston. Just after 4 p.m., I got an e-mail message from Madeleine Ball, a Harvard University researcher, telling me that the results of my genome sequencing were ready. The procedure is gaining use in cancer clinics and children’s hospitals, and will become increasingly common as the cost drops to $1,000, no more than that of many diagnostic procedures, such as MRI or colonoscopy, manufacturers and researchers say.

Before even a minute had gone by, the lengthy report was there for me to view.

“Here it is,” I thought, clicking on my inbox. “Mortality in an e-mail.”

Even as my DNA was chopped up, labeled, photographed and decoded by machines in California, the speed and power of sequencing was exploding. Life Technologies Corp. (LIFE) said Jan. 10 that its new Ion Proton machine will be able to sequence an entire genome in a day, for $1,000. Last month,Roche Holding AG (ROG) made a $5.7 billion hostile bid forIllumina Inc. (ILMN), which said it will also soon have machines that can provide 24-hour genome sequencing. Google Inc. (GOOG) and Amazon.com Inc. were investing in technologies to manage the tidal wave of information coming from these machines.

Personal Struggle

Now my own deciphered genome, the chemical instructions for making all the cells and tissues of my body, was complete. That evening marked the start of a medical and personal struggle to understand the report’s findings. The genome rules our bodies in ways that remain enigmatic. Many of the diseases and medical conditions I thought would emerge in the analysis, didn’t. At the same time, there were unpleasant surprises that cast a shadow on my future and now confront me and my family with tough medical decisions.

Before my sample was taken, I met with Denise Lautenbach, a genetic counselor who works in research programs at Harvard Medical School. We’d discussed the possible revelations that might come. My father, grandfather and some uncles have suffered from a shaking disorder called essential tremor. I worried about other conditions that run in my family, such as thyroid disease, diabetes and depression. While dementia isn’t a theme, I was curious about whether I have the APOE4 gene variant that raises the risk of Alzheimer’s disease.

Breast Cancer Risk

I also prepared by speaking with others who have had their genomes sequenced. Greg Lucier, chief executive officer of sequencer maker Life Technologies, discovered he has a gene that might raise the risk of breast cancer in himself and his daughter. Would I find out the same thing? What about far rarer conditions, such as amyotrophic lateral sclerosis and Huntington’s disease, both of which can be predicted by sequencing?

My mind raced as I scanned the results that late Monday afternoon, looking for familiar words and phrases that might be connected to other conditions that run in my family.

Good Report

It appeared to be a good report. I saw a genetic variant linked to slightly higher-than-normal risk of an age-related eye disease called macular degeneration. No surprise; about 10 percent of the U.S. develops this condition, and my mother has it. There was a variant linked to higher schizophrenia risk; again, not a huge boost in odds of a disease that affects about 1 percent of the population (and which I’m probably too old to develop). There were gene variants linked to liver and bowel disease, neither of which I suffer from.

Then my eyes were drawn back to the top of the report and a variant called JAK2-V617F. I realized then that the list was ranked in order of medical importance. Clicking on an entry brought me to a few pages of medical information, and those pages were linked to published scientific and medical studies. I began reading about JAK2 more closely.

This wasn’t good. The report classified the JAK2 variant’s clinical importance as “high,” and its impact as “well- established pathogenic,” meaning harmful. It’s seen frequently in people with rare “cancer-like” blood diseases. Indeed, as the report said, doctors test for the JAK2 variant to confirm cases of these diseases, called myeloproliferative disorders.

Unclear View

Did that mean that I already had a rare disease? My eyes widened. I read on.

Researchers currently see the variant as “one of an accumulation of changes that leads to the development of these cancer-like diseases,” the report said. “It is unclear how to view the presence of the variant in people who don’t have symptoms of the disease.”

After about 40 minutes of reading and thinking, I remained mystified. The report said “cancer-like.” I kept staring at the word “cancer,” while the companion “like” seemed to disappear. I’ve written about other people’s illnesses for years. What had started out as a cutting-edge science story was beginning to feel more like an unsettling visit to the doctor’s office with its confusion, struggles to understand, and shivers of dread.

Puzzling Medical News

“How worried should I be?” I kept thinking. Anticipation had been building inside me for months. Now my results were here and I barely knew what to make of the most important one.

I picked up the phone and called my wife, Judi, who’s a nurse. After 21 years of marriage, we’re accustomed to regular discussions of medical issues, in part because Judi has type 1 diabetes, which requires daily monitoring and insulin. Still, this was some of the most serious and puzzling medical news I’d ever received. I was careful to keep from sounding frightened.

“I got my results,” I said when she picked up the phone. I poured out the details, focusing on the JAK2 variant.

Judi’s voice was calm. I didn’t have any of the symptoms of diseases associated with the gene, she said. I’m usually energetic and active; that meant it wasn’t clear what the variant meant in my case.

“At least if there is a problem, we’ll find it earlier if you’re evaluated yearly,” she said.

“They told me that none of these results should be used to make medical decisions,” I said. “I’ll meet with the researchers later this week to talk about everything.”

New Chapter?

We agreed that, overall, the report was good news. I didn’t realize there was more news to come.

I left the office and got on my bike, which I had ridden to work that day. I pedaled carefully to make it home safely through the streets of Boston, which is never guaranteed, genes or no genes.

Three days after getting my results, I took a seat in the office of George Church, the Harvard scientist who started the Personal Genome Project that arranged my sequencing. Joe Thakuria, the clinical geneticist and project medical director who took my blood sample in this same office in September, was there to lead the discussion of my results. The team had been through meetings like this before, having analyzed and released the genomes of 10 people, including Church, in 2008. I was already feeling a stomach full of emotions: was this about to be a new chapter in my life? And if so, how long would that chapter be?

Thakuria asked if I had any questions before we began. I told them how thrilled I was that I hadn’t seen certain genes that I expected given my family’s medical history, such as the variant for essential tremor. I’d seen nothing in my report about Alzheimer’s risk, which I considered a good sign.

Not Bad News

The researchers stopped me. The technology used to sequence my DNA has difficulty penetrating certain portions of the genome. One such region contains the gene that makes a blood fat called apolipoprotein E. Consequently, my results might not show whether I have the version of a gene, called APOE4, which raises the risk of Alzheimer’s disease.

Never mind, I thought. I can live without that knowledge.

The absence of the gene for benign tremor, the condition my father and grandfather had, wasn’t necessarily such good news, the team explained. As-yet unknown genes might cause the same condition. No news wasn’t always good news; it just wasn’t bad news.

‘Very Rare’

With the three of us, along with Ball and Alexander Zaranek, another project researcher, crowded around the table in Church’s office, the team then turned to the JAK2 variant. The appearance of the gene in my blood had surprised even the Harvard scientists.

“This is probably the most serious variant that we’ve actually seen to date in the study,” Thakuria said. “It’s very rare.”

The JAK2 gene contains the DNA code for making a protein used to send signals through cells. About two out of 1,000 people have the V617F variant, which was discovered in 2005 and appears to encourage blood cells to grow and divide.

Many scientists believe it’s an acquired gene variant, meaning that I wasn’t born with it and my children and other blood relatives probably don’t have it. While JAK2 may have arisen in response to my own habits, at this point, it’s unclear what may have led to the mutation.

Blood Disorders

The JAK2 variant is found in about 90 percent of people with polycythemia vera, an oversupply of red blood cells. This disease is usually treated with drugs or phlebotomy, the draining of some blood from the system. It’s also frequently found in patients with essential thrombocytosis, an overproduction of platelets that usually requires no treatment and can be addressed with blood-thinners when patients have symptoms. It’s also used to diagnose primary myelofibrosis, the condition Sanders, the former firefighter, had. About 10 percent of these cases can develop into dangerous leukemias.

That’s three conditions linked to one gene. One of the three has a possibility of becoming cancerous, Thakuria said.

“I don’t want you to fret about this,” he said. It was the first of several times I would hear him say it.

At that point, Thakuria opened up a link to a 2010 study attached to the report. Scientists have been conducting studies of individual genes for years. The team had found a study of 10,507 people in Copenhagen who gave blood samples and then were followed for as long as 18 years. The Copenhagen researchers went back and analyzed the blood samples; 18 had the JAK2 variant.

‘Very Scary Figure’

What it showed was that 14 of the 18 people with the variant developed cancer in their lifetimes. All of the 18 died within the study period.

“That’s a very scary figure,” Thakuria said.

Information was starting to wash over me without really penetrating. I struggled to keep thinking of good questions for the team. Instead, I started asking myself questions: “What am I doing here? What are these people telling me?” I searched the faces arrayed around me, trying to see whether any of the researchers looked as panicked as I felt.

I tried to listen closely as Thakuria explained what the variant and the study might mean. There were a number of shortcomings in the Copenhagen study that made it difficult to interpret, he said. For example, he said, the authors had been liberal in their use of the word “cancer.” Some of the disorders developed by patients with the JAK2 variant were of the milder variety such as polycythemia vera, which isn’t typically classified as a cancer.

Issue of Deaths

Then there was the issue of deaths. It wasn’t clear whether people with the variant had died of the conditions they had been diagnosed with, or other causes, Thakuria said. Half of them had died in their 80s, and seven had died in their 70s. This is not far from average life expectancy, he pointed out.

“Half of them could have died of bicycle accidents,” he said, smiling.

There were other reasons not to fret, Thakuria said. Although the JAK2 variant often shows up in these conditions, no one knows precisely what role it plays. It may be a cause of the disorders, or an effect of changes elsewhere in the genome. The JAK2 variant was unlikely to be the only cause of these diseases; several things — things that remain unknown to us — would probably have to go wrong before any disease would arise. In this context, the gene wasn’t quite so scary, Thakuria said.

Black and White

I thought about a conversation I’d had with Ball just a few days earlier, while my genome were still being analyzed. I had called to see when the results were coming. She said they were “interesting,” but didn’t want to discuss them until a clinical geneticist had a chance to review them. Her voice sounded like she didn’t want to reveal everything she knew.

“I wish everything were black and white,” she said. “Unfortunately, things just don’t turn out that way very often.”

The researchers said I now needed to confirm that the sequencing was correct with another round of testing using a different technique. I would give another blood sample. If the variant was there, we’d talk more about what steps to take.

The meeting lasted almost two hours, and I left Church’s office with Thakuria. We walked to a restaurant about halfway between Harvard Medical School and Fenway Park to sit and have a drink. I continued to quiz him on the relationship between the JAK2 variant and the diseases we’d been talking about.

Ask Again

Sitting on a barstool next to Thakuria and listening to him discuss the JAK2 variant, I felt reassured. It occurred to me that this wasn’t how most people would receive the news of their results. As a reporter working on a story about genomics, I had access to experts that many people wouldn’t. What will happen as more people get results from broad genome sequencing?

I spoke about this during a meeting with Harold Varmus, director of the U.S. National Cancer Institute, and a co-winner of a Nobel Prize in 1989 for his work to find genes that promote the growth of cancer cells. I mentioned I had just received my results.

“How do you feel?” he asked.

“It’s been an interesting process,” I said. “It’s still playing out.”

Varmus nodded. Gathering genetic data from thousands of people can help researchers understand health by correlating gene variations with diseases, he said. He was concerned, however, that companies may not always ensure that people who have undergone sequencing will get a full understanding of their results.

‘How to Deal’

“Accumulating the information and studying it is good,” he said. “My concern is whether individuals are getting guidance on how to deal with the information.”

“People are being told they have a certain gene variant. In a mass population, that increases the risk of some diseases by, say, two-fold. That might be true in a mass population, but in any single individual’s genome, it’s not certain what that means.”

The Harvard researchers are struggling with these same issues, and are still working to streamline and improve their approach to giving results to study participants, Thakuria said.

“As we get more information from participants like you, we’ll gain a much better understanding of how to do it,” Thakuria said.

Animal Studies

I still felt like someone who kept shaking a toy Magic 8 Ball and getting the message: “Concentrate and ask again.” I decided to do a little research on my own. I found a 2010 study in the journal Blood showing that when the JAK2 variant was added to the genomes of mice, the animals later suffered from disorders similar to those seen in people with the gene.

This is just one of several animal studies suggesting that the JAK2 variant contributes directly to blood disorders, said John Crispino, a professor at Northwestern University Feinberg School of Medicine, who studies the gene. Skeptics point out that drugs that interfere with JAK2 don’t cure patients suffering from the gene-linked blood disorders.

“The field is mixed,” he said. “My bias is that the JAK2 variant contributes to the pathology of the disease.”

I wanted to find out what kind of people have the JAK2 mutation I have, and what’s happened to them. In addition to Sanders, the Indiana firefighter, I spoke with Bob Rosen, chairman of theMPN Research Foundation, a Chicago-based advocacy group for people with myeloproliferative disorders, and he had a surprise for me.

Red Blood Cells

About 14 years ago, Rosen went to a doctor because of pain in his fingers and toes. A complete blood count revealed high levels of red blood cells. He was diagnosed with polycythemia vera and was first treated with phlebotomy. He now takes a drug that controls his blood cell levels. With his treatment, he’s still able to work out, and had been playing basketball on the day I called him.

“I’ve been lucky,” he said. “The risk is that, over time, new symptoms will emerge or there will be a progression to something worse.”

A small percentage of patients with polycythemia vera can develop more serious conditions, such as primary myelofibrosis and certain leukemias, Rosen said. I hadn’t realized this, or hadn’t absorbed it, until now.

Another Surprise

Then, another surprise arrived. Looking at my report, I saw it had been updated electronically, as the genome project research team had told me would happen from time to time. Now, the second entry on my list of variants was labeled “APOE- C130R” — that’s another name for the APOE4 gene associated with increased risk of Alzheimer’s disease.

I kept reading, recalling that I had been told my ApoE result wasn’t accessible with the technology used to sequence my genome. As it turned out, the technology had worked after all. I was at increased risk for Alzheimer’s.

This was exactly the kind of news I had hoped I wouldn’t receive.

A few days later I got an e-mail from Ball, of the Harvard team.

“Sorry this was missed earlier,” she said in the e-mail. She recommended that I look at the studies she’d collected on APOE4, some of which casts doubt on the role of the variant as a strong factor in causing Alzheimer’s. According to one estimate, people who have one copy of the gene, as I do, have a 3 percent increased risk of developing the disease by age 80.

Better to Know

One of my parents must have had this gene variant in order for me to get it. Yet my mother is in her late 70s and my father is 80; neither of them has Alzheimer’s disease. The longer I thought about it, the less I worried.

I talked with my two children, Hanna and James, about their feelings regarding the JAK2 and Alzheimer’s gene variants. My daughter, a sophomore in college, said she thinks it’s an advantage to be aware of a health threat.

“If there’s a treatment for it, you could start earlier,” she said. “It’s better to know.”

My next stop was to see my doctor. While she didn’t want her name used in this story, she agreed to let me write about our conversations and paraphrase her comments.

I followed an aide into an exam room. Nothing about my body had changed since the genome test was done. I still had normal blood pressure and pulse, and my weight was steady.

My doctor had heard of the JAK2 variant. If the result was confirmed, I would need to have my blood count tested. If there was an oversupply of red blood cells or platelets, or signs of damaged bone marrow, we would start thinking about treatment, such as removing blood. She asked me how I was feeling.

‘Not Sick’

“I feel fine,” I said. “I’m not sick.”

I didn’t mention that every time I thought about the JAK2 variant, itching followed. I had read that itching was one of the symptoms of polycythemia vera. Even as I write these words, I’m scratching my forehead. I never feel itchy when not thinking about my genome. I also started noticing memory lapses.

This kind of behavior is often called “medical student syndrome,” because doctors in training who are learning to diagnose new diseases turn their skills on themselves. I assumed it was this syndrome I was suffering from, rather than a blood disorder.

It seemed like a good time to return to the Boston office of Aubrey Milunsky, the director of the Boston University Center for Human Genetics who had warned me in May that having my genome sequenced would just cause me needless worry.

“Why would you want to know that?” he had asked me then.

Milunsky was well-acquainted with the JAK2 variant on my report. Just as the team at Harvard had said, he mentioned that there was little known about the long-term impact of the variant in people. He noted that it’s also associated with some cases of dangerous clotting in abdominal blood vessels.

“You know it’s there, but you don’t know what it means,” he said. “You’re smack in the territory of inviting anxiety into your life. And this may have no meaning whatsoever in your entire life.”

Useful Vigilance

I disagreed. The results had actually taken some uncertainty out of my life, I told Milunsky. We all bear some health risks, and that’s why doctors recommend, for instance, that everyone get regular checkups and those 50 and older undergo tests for colon cancer. I have a rare mutation linked to rare conditions, most cases of which can be treated. Wouldn’t it make sense for me to undergo a blood test regularly to see whether my blood counts had changed?

Such vigilance might be beneficial, and it might not, Milunsky said. I might live the rest of my life with my health unaffected by the variant. Yet the exercise had shown that I had discovered things I’d rather not know, he said. Others who undergo the same procedure will surely find out that they have mutations that practically guarantee they will develop serious and perhaps even fatal diseases, he said.

Huntington’s Disease

Indeed, a 1999 study in the American Journal of Human Genetics found that about 1 percent of 4,527 people who were told they had the gene that causes Huntington’s disease, a progressive nervous system disorder, attempted or committed suicide, or were hospitalized for psychiatric reasons.

Medical researchers are still trying to determine when it makes sense to do more common tests for breast and prostate cancer. A certain percentage of people who get positive results on these screening exams will go on to have unneeded treatment that may cause harm. In October, a government panel recommended that blood tests used to screen for prostate cancer should only be performed on men with symptoms. The same panel said in 2009 that women should start getting mammograms at age 50, rather than 40.

On Jan. 25, at about 11 p.m., I got a phone call from Thakuria. We had arranged to speak late in the day to accommodate busy schedules.

‘Mutation Confirmed’

“The mutation confirmed,” he said. He didn’t say “JAK2,” but I knew that was what he was talking about.

The next step for me is to have my white and red blood-cell levels measured, along with those of platelets. Doctors will also study the appearance of these cells under a microscope and check to see how much oxygen my blood can carry. I expect these tests to be normal. If they aren’t, it’s possible that I’ll start getting blood drawn from my system or drug treatment for polycythemia vera. I may need to take a blood thinner, such as aspirin, to counteract the effects of excess platelets. Should I have evidence of more serious disease, stronger treatment may be needed.

“I’m not going to lie to you: I’d rather you didn’t have it,” Thakuria said. “This isn’t like one of those mutations that have specific recommendations. There are no guidelines here. This is part of being on the frontier.”

To contact the reporter on this story: John Lauerman in Boston at jlauerman@bloomberg.net

To contact the editor responsible for this story: Jonathan Kaufman at




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Barcode Of Me

Barcode Of Me (Photo credit: Purple_Mecha)

Larry H Bernstein, MD, FACP, Reporter

from the DARK Report (—Pamela Scherer McLeod)


Harvard Researchers’ New DNA Barcoding May Give Pathologists Expanded Capabilities in Fluorescence Microscopy 

November 5, 2012

New biomedical imaging technology could enhance pathologists’ ability to examine tissue samples via fluorescence microscopy
Scientists at Harvard University’s Wyss Institute for Biologically Inspired Engineeringhave developed a new DNA, barcoding technique. The fluorescence microscopy approach has significant implications for the imaging community.

Beyond imaging, however, pathologists will be able to use this same technology when evaluating tissue specimens.

The new method could enable simultaneous imaging of many different types of molecules in a single cell, according to Peng Yin, Ph.D., Associate Professor of Systems Biology at Harvard Medical School and Core Faculty Member at Wyss Institute. The developers expect the method to provide researchers with a richer, more accurate view of cell behavior than is possible using current techniques.

Pathologists Could Adopt DNA Barcoding for In Vitro Diagnostics

“We hope this new method will provide much-needed molecular tools for usingfluorescence microscopy to study complex biological problems,” stated Yin, the study’s co-author, in a recent press release.

1903 Siedentopf Fluorescence Microscope

1903 Siedentopf Fluorescence Microscope (Photo credit: Carl Zeiss Microscopy)



Using DNA Origami to Create Fluorescent Linear DNA Barcodes
The newly engineered DNA barcode harnesses the natural ability of DNA to self-assemble. The basis of the new technology is a process called DNA origami. This enables scientists to arrange colored dots, or fluorophores, into geometric patterns, or fluorescent linear DNA barcodes.

These imaging probes translate a cell’s invisible biological information, such asproteins or RNA molecules, into detectable signals, noted a summary of Yin’s research on the Wyss website. These signals help researchers better understand the role of cell behavior in the onset and progression of disease.

New Barcode Could Offer a Virtually Unlimited Number of Styles

Scientists currently use fluorescence microscopy to pair fluorescent elements—the barcodes—with molecules they know will attach to the part of the cells they want to investigate. When they illuminate the sample, it triggers each kind of barcode to fluoresce at a particular wavelength of light, which indicates the location of the molecules of interest.

Click Here for Photo
Researchers at Harvard’s Wyss Institute recently engineered a new DNA barcode. Labeled DNA samples appear as multi-colored barcodes under fluorescent light at certain wavelengths. Pathologists and clinical laboratory professionals will recognize the potential of this technology in the examination of tissue specimens. (Photo credit: Rick Groleau, Harvard University.)

However, the multiplexing ability of fluorescence microscopy is limited by the number of spectrally distinguishable fluorophores, a story in Nature Chemistry explained. The barcodes that scientists currently use have only three or four colors available, such as red, blue, or green. And sometimes those colors blur. This limits the number of objects scientists have been able to study in a cell sample at one time.

Multiplex Capability with 216 Readable Color Combinations

Using the new method, Yin was able to demonstrate 216 color combinations resulting from attaching just three colors to a DNA nanotube, the press release stated. With the new barcode, the combinations are almost limitless. This will significantly advance the ability to fluoresce more cellular structure than previously possible.

DNA origami works by programming a long strand of DNA to self-assemble by folding in on itself, the release stated. Shorter strands, called staples, help it to create predetermined forms. Researchers then attach fluorescent molecules to the desired spots on the now more structurally complex DNA nanostructures. In this way, they use origami technology to generate a large pool of barcodes out of only a few fluorescent molecules.

“We can essentially use DNA joints to assemble the nanostructures into long rods, and we can modify the rods with fluorescence at different locations,” declared Yin. “We then use these tiny rods to arrange the fluorescent spots into colorful barcodes. Basically now using three or four colors, we can have hundreds of different barcodes,” he observed in a story in The Harvard Crimson.

A New Tool in the Cellular Imaging—and In Situ Examination—Toolbox

“[The technique] holds great promise for using the method to study cells in their native environments,” Yin observed. Additionally, the technique is low-cost, easy to do, and more robust compared to current methods, according to Yin.

Pathologists and clinical laboratory managers will recognize the range of potential of this new technology, from developing targeted drug-delivery mechanisms to improving the scope of cellular and molecular activities scientists are able to observe at a disease site.

—Pamela Scherer McLeod


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Reporter: Aviva Lev-Ari, PhD, RN


Economics and genetics meet in uneasy union

Use of population-genetic data to predict economic success sparks war of words.

10 October 2012 Corrected: 

  1. 12 October 2012
The United States has the right amount of genetic diversity to buoy its economy, claim economists.


“The invalid assumption that correlation implies cause is probably among the two or three most serious and common errors of human reasoning.” Evolutionary biologist Stephen Jay Gould was referring to purported links between genetics and an individual’s intelligence when he made this familiar complaint in his 1981 book The Mismeasure of Man

Fast-forward three decades, and leading geneticists and anthropologists are levelling a similar charge at economics researchers who claim that a country’s genetic diversity can predict the success of its economy. To critics, the economists’ paper seems to suggest that a country’s poverty could be the result of its citizens’ genetic make-up, and the paper is attracting charges of genetic determinism, and even racism. But the economists say that they have been misunderstood, and are merely using genetics as a proxy for other factors that can drive an economy, such as history and culture. The debate holds cautionary lessons for a nascent field that blends genetics with economics, sometimes called genoeconomics. The work could have real-world pay-offs, such as helping policy-makers to “reduce barriers to the flows of ideas and innovations across populations”, says Enrico Spolaore, an economist at Tufts University near Boston, Massachusetts, who has also used global genetic-diversity data in his research.

But the economists at the forefront of this field clearly need to be prepared for harsh scrutiny of their techniques and conclusions. At the centre of the storm is a 107-page paper by Oded Galor of Brown University in Providence, Rhode Island, and Quamrul Ashraf of Williams College in Williamstown, Massachusetts1. It has been peer-reviewed by economists and biologists, and will soon appear in American Economic Review, one of the most prestigious economics journals.

The paper argues that there are strong links between estimates of genetic diversity for 145 countries and per-capita incomes, even after accounting for myriad factors such as economic-based migration. High genetic diversity in a country’s population is linked with greater innovation, the paper says, because diverse populations have a greater range of cognitive abilities and styles. By contrast, low genetic diversity tends to produce societies with greater interpersonal trust, because there are fewer differences between populations. Countries with intermediate levels of diversity, such as the United States, balance these factors and have the most productive economies as a result, the economists conclude.

The manuscript had been circulating on the Internet for more than two years, garnering little attention outside economics — until last month, when Science published a summary of the paper in its section on new research in other journals. This sparked a sharp response from a long list of prominent scientists, including geneticist David Reich of Harvard Medical School in Boston, Massachusetts, and Harvard University palaeoanthropologist Daniel Lieberman in Cambridge.

In an open letter, the group said that it is worried about the political implications of the economists’ work: “the suggestion that an ideal level of genetic variation could foster economic growth and could even be engineered has the potential to be misused with frightening consequences to justify indefensible practices such as ethnic cleansing or genocide,” it said.

“Our study is not about a nature or nurture debate.”

The critics add that the economists made blunders such as treating the genetic diversity of different countries as independent data, when they are intrinsically linked by human migration and shared history. “It’s a misuse of data,” says Reich, which undermines the paper’s main conclusions. The populations of East Asian countries share a common genetic history, and cultural practices — but the former is not necessarily responsible for the latter. “Such haphazard methods and erroneous assumptions of statistical independence could equally find a genetic cause for the use of chopsticks,” the critics wrote.

They have missed the point, responds Galor, a prominent economist whose work examines the ancient origins of contemporary economic factors. “The entire criticism is based on a gross misinterpretation of our work and, in some respects, a superficial understanding of the empirical techniques employed,” he says. Galor and Ashraf told Nature that, far from claiming that genetic diversity directly influences economic development, they are using it as a proxy for immeasurable cultural, historical and biological factors that influence economies. “Our study is not about a nature or nurture debate,” says Ashraf. 

“It seems like the devil is in the interpretation more than the actual application of the statistics,” says Sohini Ramachandran, a population geneticist at Brown University who provided the genetic data for the study. She adds that Galor and Ashraf used estimates of genetic diversity that she and her colleagues specifically developed to overcome many of the confounding factors caused by the overlapping genetic and cultural histories of neighbouring countries.

Galor and Ashraf are not the first economists to use genetic-diversity data. Spolaore has also found that the differences in genetic diversity between countries can predict discrepancies in their level of economic development2. But he is clear that this is not necessarily a causal relationship:  “In my view it’s not genetic diversity itself that is responsible for this correlation,” he says. “A lot of this could be culture.”

Some say that the field needs a dose of rigour. Many studies linking genetic variation to economic traits make basic methodological errors, says Daniel Benjamin, a behavioural economist at Cornell University in Ithaca, New York. He is part of the Social Science Genetics Association Consortium, a group that brings together social scientists, epidemiologists and geneticists to improve such studies. Problems that medical geneticists have known about for years — such as those stemming from small sample sizes — crop up all too often when economists start to work with the data, he says.

For instance, while searching for genetic associations with factors such as happiness and income in a study of 2,349 Icelanders, Benjamin and his colleagues found a statistically significant association between educational attainment and a variant in a gene involved in breaking down a neurotransmitter molecule3. But the researchers could not replicate this association in three other population samples — a test for false positives that is standard practice in medical genetics — and the team now has reservations about the association. If the field is to develop fruitfully, “I think it’s essential for us to have geneticists involved”, says Benjamin. “We couldn’t do it without their help and insight.”

Nature 490, 154–155 (11 October 2012) doi:10.1038/490154a


In the original text, we wrongly attributed to Enrico Spolaore the opinion that using genetic data in economics could help policy-makers to set immigration levels. He actually suggested that the work could reduce barriers to the flows of ideas and innovations across populations. The text has been amended to reflect that.


  1. Ashraf, Q. & Galor, O. Am. Econ. Rev. (in the press).

    Show context

  2. Spolaore, E. & Wacziarg, W. Q. J. Econ. 124, 469–529 (2009).

    Show context

  3. Benjamin, D. J. et al. Annu. Rev. Econ. 4, 627–662 (2012).

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