MEDICAL BEAT May 9, 2014

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April-

June 2014

Issue 1

Also in this issue:

The Science Behind Tomorrow’s Medicine

June 2014, Sample Issue

MITIGATING THE DEADLY EFFECTS OF RADIATION EXPOSURE

New Drug Provides Protection against Radiation Sickness pg.11

Issue 1

STRATEGIES TO COMBAT THE

ROOT OF ASTHMA

Breathing Better with Early-Life

Prevention and New Treatments

pg. 22

CATCHING THE HACKERS

BEHIND CANCER

METASTASIS

New approach to stop cancer’s

invasion into the bloodstream

Page 10

FORGETFULNESS BEGINS WITH

NEW NEURONS

Exercise Produces New Neurons to Erase

Unused Memories

pg. 16

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About the Cover

The cover depicts an image of the workers at the

Fukushima nuclear plant following the 2011 nuclear

disaster. Scientists recently discover a new drug that

can protect these workers from the lethal effects of

radiation exposure.

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EDITORIAL Executive Editor- Jennifer WJ Wong (PhD)

ABOUT THE EDITOR

Jennifer received her PhD in Neuroscience in 2010 at the University of British

Columbia in Vancouver, Canada. While working on her postdoctoral fellowship at

the Brain Research Centre (UBC), Jennifer began her career as a scientific writer

by starting her online blog on Science2.0, and has since published in Science

Magazine and the Lancet Oncology. She later joined the Nature Publishing Group

in London (UK) as a temporary scientific editor. Today, Jennifer is the executive

editor of her newly launched magazine The Medical Beat.

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CONTENTS June 2014, Sample Issue

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Forgetfulness Begins with New Neurons Exercise Produces New Neurons to Erase Unused Memories

Mitigating the Deadly Effects of Radiation Exposure New Drug Provides Protection against Radiation Sickness by

Protecting the Gut Epithelium from Radiation Damage.

Snapshots- Wireless device to recharge deeply implanted pacemakers, and 1018 eliminates bacteria biofilm

Editor’s Pick Primitive Viruses Point to a New Cancer Treatment

Combating the Root of Asthma Breathing Better with Early-Life Prevention and New Treatments

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A Wireless Technology to

Recharge Pacemakers

Dr. Ada Poon and colleagues at Stanford University created a miniature

wireless power transfer technology to safely recharge deeply implanted

devices including pacemakers. Credit: Image courtesy of Austin Yee.

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When a pacemaker runs out of power, the

simple act of replacing the pacemaker’s

batteries is an invasive surgical procedure. An

ideal alternative would be to recharge implanted

pacemakers using a wireless power transfer

technology. But the technology that is available

so far is not powerful enough to deliver

sufficient energy to deeply implanted devices, or

small enough to be safely implanted.

In this study, Poon and colleagues designed a

new wireless power transfer technology that can

successfully charge deeply implanted

pacemakers by focusing electromagnetic energy

deep into tissue. The wireless technology

consists of a patterned metal plate that uses

midfield power transfer to focus

electromagnetic energy to a specific region deep

in tissue, where the energy could be taken up by

an implanted power-harvesting device. By

focusing electromagnetic energy, Poon and

colleagues are able to remotely transfer up to

2000 microwatts of power to a miniature power-

harvesting device that is implanted into 5cm of

tissue.

The size of a rice grain, this miniature power-

harvesting device can be safely implanted into

the heart. The device can effectively power

pacemakers- which only need about 8

microwatts of power. The study is published in

the May 19th 2014 issue of the Proceedings of

the National Academy of Sciences1.

1. Ho J.S. et al. Proceedings of the National Academy of Sciences

(2014) in press.

Smaller than the size of a pill, this tiny implantable

device can be remotely charged deep inside the

body using a new wireless power transfer

technology. The device can be used to safely power

deeply implanted devices such as pacemakers.

Credit: Image courtesy of Austin Yee.

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1018: Bacteria Biofilm Busters

Dr. Robert Hancock at the University of British Columbia discovered a

peptide, 1018, that could stop bacteria from forming biofilms.

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Previous page: Bacteria

such as E. coli form

communities called

biofilms in response to

stress.

Right: 1018 stops biofilm

building. Bacteria such as

Pseudomonas aeruginosa

and MRSA can’t form

biofilms in the presence of

1018. (Credit: César de la

Fuente-Núñez)

A biofilm is a community of harmful bacteria

that is implicated in 65% of bacterial infections

in humans. These communities represent a

microbial survival tactic that can help bacteria

resist the host’s anti-microbial defense and even

antibiotics. Often sticking to various surfaces like

human skin and surgical instruments, these

bacterial biofilms are considered a major health

concern worldwide.

The formation of a biofilm is triggered by a

bacterial stress signal known as (p)ppGpp- a

signal that is evolutionarily conserved across all

species of bacteria. As a defense mechanism

against these infectious biofilms, nature has also

created biofilm-inhibiting peptides to stop the

formation of bacteria biofilms.

In a study published in the May 2014 issue of

PLOS Pathogens, Dr. Hancock and colleagues

successfully identified a human peptide with

broad-spectrum biofilm blocking activity- a

peptide known as IDR (innate defense

regulator)-10181. Also known simply as 1018,

this peptide could directly trigger the

degradation of the bacterial stress signal

(p)ppGpp responsible for biofilm formation.

Hancock further shows that 1018 can prevent

biofilm formation in wide range of bacteria,

including E.coli, MRSA, and Pseudomonas. 1018

is also powerful enough to disperse bacteria

biofilms that are at least 2 days old, and to

promote bacterial cell death. The discovery of

1018 could point the way to eliminating biofilms

and minimizing infections.

1. de la Fuente-Nunez C. et al. PLOS Pathogens 10,

e1004152. (2014)

The Medical Beat 9

Primitive Viruses Point

to a New Cancer

Treatment Virus-Derived Peptibodies

Deplete Immune Cells That

Promote Cancer Growth

Our immune system is constantly on

the lookout for cancerous cells in

our bodies, eliminating them before

they become a disease. A prevailing

concept in the late 1990’s suggests

the cancer has the ability to evade

the immune system1. Scientists now

know that cancers release immune

signals to stimulate the recruitment

of a mixed white blood cell

population called myeloid derived

suppressor cells (MDSCs)2.

Like a cloak of darkness shielding

invaders from surveillance cameras,

MDSCs are immune suppressive cells

that are implicated in helping cancer

evade immune surveillance3,4. Specifically,

MDSCs can inhibit immune surveillance by

suppressing and killing T cells- an immune cell

population that can recognize and attack tumor

cells5,6. MDSCs can also activate regulatory T

cells (Treg)- an immune cell population known to

silence the immune system against the cancer7.

Given the well-accepted role of MDSCs in

cancer’s immune evasion, Dr. Larry Kwak and

colleagues at the University of Texas MD

Anderson Cancer (Houston, TX) wondered if

they could thwart the cancer’s ability to evade

the immune system simply by removing MDSCs.

To answer this question, one challenge that

Kwak faces is the lack of proper tools to

effectively deplete MDSCs. “We’ve known about

[MDSCs] for a decade, but haven’t been able to

shut them down for lack of an identified target,”

said Kwak.

In the study published in the May 28th issue of

Nature Medicine8, Kwak’s team set out to

identify an MDSC-specific marker by probing the

surface of MDSCs with a library of primitive

viruses known as phages. Each phage typically

displays a unique array of peptides that can

recognize specific cell surface markers. By

probing the surface of MDSCs with a library of

phages, Kwak discover that phages expressing

either the G3 or H6 peptides can bind

Phages (small particles depicted here) are primitive viruses that

display specific peptides on their surface. Kwak identified 2 phage

peptides (G3 and H6) that can bind specifically to MDSCs.

The Medical Beat 10

specifically to MDSCs.

To create “antibodies” that can specifically

recognize MDSCs, the team designed an

antibody-peptide fusion (peptibody) that

incorporates G3 and H6 peptides into the part of

the antibody that is involved in recognizing

antigens. The idea is to create an “antibody”

version of G3 and H6 peptides, called Pep-G3

and Pep-H6 peptibodies, which can recognize

and bind to MDSCs specifically.

Unlike the G3 and H6 peptides, however the

Pep-G3 and Pep-H6 peptibodies actually behave

like antibodies. Antibodies typically work by

flagging cells for immune destruction- in a

process dubbed antibody-dependent cell-

mediated toxicity (ADCC)9. During ADCC, cells

that are flagged with antibodies could be

recognized by an immune cell population known

as natural killer (NK) cells, which release toxins

to kill the antibody-bound cell. Similar to

antibodies, Pep-G3 and Pep-H6 peptibodies can

flag MDSCs for immune destruction, depleting

MDSCs from the system.

To see if the peptibodies can specifically deplete

tumor-associated MDSCs in mice, Kwak injected

the Pep-G3 or PepH6 into a mouse model of

thymus cancer- a model created by implanting

EL4 thymus cancer cells under the mouse skin.

Following peptibody injections, Kwak discover

that either Pep-H6 or Pep-G3 could deplete

MDSCs over the course of 2 weeks. The

peptibodies did not deplete other immune cells,

demonstrating the incredible cell-type specificity

of these peptibodies.

That’s really exciting because [the peptibodies

are] so specific for MDSCs that we would expect

few, if any, side effects,” said Dr. Kwak.

Kwak further shows that the MDSC depletion is

associated with a significant decline in cancer

growth in mice, suggesting that MDSC-depleting

peptibodies could potentially be a new class of

drug to combat cancer.

Further investigating how the peptibodies affect

cancer growth, Kwak also discovered that Pep-

G3 and Pep-H6 peptibodies appear to recognize

specifically the S100A8 and S100A9 proteins

respectively. S100 proteins are typically

expressed in cancer cells to recruit MDSCs2, to

boost MDSC recruitment.10 The same signals are

also produced by MDSCs to help cancer cells

survive and grow11. Kwak explains that the

peptibodies could sequester these important

survival signals, and consequently hinder cancer

growth in mice.

The question that remains to be answered is

whether MDSC-depleting peptibodies could also

reactivate the immune response against the

cancer. Although further work is needed to

answer this compelling question, Kwak is

optimistic that peptibodies could help unleash

the immune system against the cancer.

The next step is to test whether the peptibodies

could deplete MDSCs in humans, and whether

this approach could successfully combat human

cancers.

By: Jennifer Wong

1. Dunn GP et al Nat Immunol. 3, 991 - 998 (2002)

2. Sinha P et al J Immunol. 181, 4666-75 (2008)

3. Kusmartsev S. J Immunol. 175, 4583-92 (2005)

4. Kusmartsev S. & Gabrilovich DI. J Immunol. 174, 4880-91 (2005)

5. Rodriguez P.C. et al Blood 109, 1568-1573 (2007)

6. Bingisser R. et al. J. Immunol. 160, 5729-5734 (1998)

7. Huang B et al Cancer Res.66, :1123-31 (2005).

8. Qin H. et al. Nat Med. (2014)- in press

9. Strome S.E. et al. The Oncologist. 12 , 1084-1095 (2007). Review.

10. Ichikawa, M et al. Mol. Cancer Res. 9, 133–148 (2011)

11. Källberg, E. et al. PLoS ONE 7, e34207 (2012)

The Medical Beat 11

Mitigating the Deadly Effects

of Radiation Exposure A New Drug Provides Protection against Radiation Sickness

by Protecting the Gut Epithelium from Radiation Damage

By: Jennifer Wong

Read the full story in the June 2014 issue of the Medical

Beat. Purchase your copy today.

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A portrait of radiation sickness: An 11-year Japanese girl

who survived the nuclear bombing in Hiroshima in

World War II.

An indelible portrait of the devastating

effects of radiation exposure is the sickly bald

face of an 11-year old Japanese girl from the

Hiroshima nuclear bombing in 1945. This image

depicts radiation sickness- a major health

concern that still haunts today’s society

especially in light of the recent 2011 nuclear

incident in Fukushima Daiichi, Japan, in what

appears to be an unfortunate aftermath of a

tsunami.

With radioactive waste water and debris being

released into the oceans, and travelling

relentlessly towards the pristine west coast

shorelines of Canada and the United States,

radiation is now becoming a global health

concern. Because there are no known FDA-

approved drugs to mitigate the harmful effects

of radiation, scientists are keen to understand

precisely how radiation kills, and what could be

done to reduce the deadly effects of radiation

exposure.

Although precisely how radiation causes death

remains unclear to this day, scientists now know

that radiation causes cell death by inflicting

damage to DNA, the genetic material of the cell

that is replicated during the process of cell

division. Rapidly dividing cells in the bone

marrow, hair follicles and the gut, in particular,

are the most susceptible to radiation damage

and are often the first to be eliminated upon

radiation exposure. Among the battery of

symptoms that define radiation sickness, the

destruction of the gut lining is considered one of

the major causes of death1,2.

In a recent study published in the May 14th issue

of Science Translational Medicine3, scientists at

Stanford University discover an intrinsic cell

stress signal that can protect the body from

radiation sickness, especially by protecting the

gut lining from radiation-induced damage. The

discovery can open a new avenue to mitigate

the life-threatening consequences of radiation.

Harnessing the Gut’s Protective Mechanism

against Radiation Damage

The gut lining, also known as the gut epithelium,

consists of epithelial cells that form a brush-like

barrier between the bloodstream and the gut

environment. This barrier helps the body absorb

nutrients and water from the food we eat, while

preventing gut bacteria from invading the

bloodstream. The destruction of the gut

epithelium from radiation exposure puts the

body at risk of severe dehydration and

electrolyte imbalance, intestinal defects causing

diarrhea and vomiting, as well as life-threatening

sepsis caused by the invasion of gut bacteria1,2.

Read the full story in the June 2014 Issue…

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Forgetfulness Begins with New Neurons

Exercise Produces New Neurons to Erase Unused Memories

By: Jennifer Wong

Read the full story in the June 2014 issue of the Medical Beat.

Purchase your copy today.

The Medical Beat

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Forgetfulness is something that we often face

over the course of our lifetime. It’s very common

to forget about the events in our early lives as

infants and toddlers, and we often rely on

parents to provide fond recollections of these

early memories. As we begin to age, we face

embarrassing moments when we search in vain

for our lost vehicle in the parking lot, or when

we forget the names of familiar faces at a

cocktail party.

Although precisely what causes forgetfulness

remains unclear, decades of research has at least

revealed some insights into how memories are

formed. We now know that memories are stored

in a brain structure called the hippocampus.

Contained in this distinctive structure are

neuronal circuits that encode memories, as well

as a neuronal germinal center to produce new

neurons. The latter is involved in producing

neurons in the adult in the process dubbed adult

neurogenesis, and is implicated in memory

formation1. The gradual decline of neurogenesis

with increasing age2, or in dementia3, is further

implicated in reducing memory.

Interestingly, scientists also discovered that

regular exercise can actually boost

neurogenesis, specifically by turning on genes

that can stimulate the neuronal germinal centers

in the hippocampus to produce new neurons4. A

body of work reveals that exercise can drive the

expression of growth factors and

neurotransmitters (serotonin) that can boost the

production of neurons4,5,6. Particularly in the

elderly, exercise appears to be an effective way

to boost neurogenesis and learning2, suggesting

that regular exercise could improve the

development of new memories as we age.

But before we flock to the gym for some

memory-boosting exercise, scientists now

caution that exercise can also cause

forgetfulness. Although exercise can boost

memory by driving the production of new

neurons to build new memories, a recent study

published in the May 9, 2014 issue of Science7

reveals that exercise-induced neurogenesis can

cause forgetfulness by impeding the retrieval of

old memories. The study also shows that high

levels of neurogenesis in the infant during early

brain development can also be the culprit

behind infantile amnesia, preventing us from

recalling the early events in our infanthood and

early childhood.

Exercise-Induced Neurogenesis Promotes

Forgetfulness in Adult Mice

n the study published in Science,7 Dr. Paul

Frankland and colleagues at the Toronto’s Sick

Kids Children Hospital (ON, Canada) discover

that exercise can promote forgetfulness. They

show this by using a series of behavioral tests to

evaluate how exercise-induced neurogenesis

could influence the retrieval of old memories in

mice.

The behavioral study involves testing mice that

are trained to associate a specific context with a

foot shock- in a behavioral paradigm called

contextual fear conditioning. Several weeks after

this training, the team evaluated whether

exercise could influence how well the mice could

remember the context (ex: a designated cage)

associated with foot shock, and whether they

could demonstrate contextual fear by showing a

“freeze” response to this context.

Read the full story in the June 2014 Issue…

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Combating the Root of Asthma Breathing Better with Early-Life Prevention and New Treatments

By: Jennifer Wong

Image credit: Тетяна Фіонік/CC-BY-SA-3.0

Read the full story in the June 2014 issue of

the Medical Beat. Purchase your copy today.

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The breath of life is something that we take

for granted. But for someone who has asthma,

breathing can be an everyday struggle, where

simple triggers like dust mites, pollen or even

physical exertions can cause a fit of wheezing

and coughing. Often diagnosed in childhood, this

recurrent disease threatens to take away the

ease of breathing at any moment, and could be

an impediment to everyday sports and activities

throughout life.

The wheezing during an asthma attack is caused

by an allergic inflammatory reaction that

constricts the airway1- a potentially life-

threatening condition that asthma sufferers

often face. The allergic inflammation is caused

by a population of allergic lymphocytes, T helper

2 (TH2) cells1. In response to allergen inhalation,

TH2 cells release signals to stimulate the

production of IgE antibodies, which in turn

activate white blood cells (such as eosinophil

and mast cells) in the airway and lungs. The

white blood cells respond by releasing

inflammatory signals such as histamine- a signal

that stimulates smooth muscles in the

respiratory tract to contract. The contraction

constricts the airway, causing an asthma attack.

The most common treatment for asthma is an

inhalable muscle relaxant, known as

bronchodilators, which can re-open the airway.

Although this inhalant could serve as an

immediate relief for asthma sufferers during an

asthma attack, it does very little to combat the

root of the inflammatory reaction that causes

asthma in the first place. Because asthma is a

recurrent disease, many asthma sufferers use

bronchodilators on a regular basis, and its

prolonged use could often promote tolerance.

The tolerance could render bronchodilators

useless against a future asthma attack2. Clearly,

a more effective treatment is needed to better

combat asthma.

With 235 million asthma sufferers worldwide,

based on an estimate from the World Health

Organization, there is an urgent need to better

An asthma attack is an

allergic inflammatory

reaction that constricts

the airway. The

constriction is caused by

the activation of

immune cells that

produce histamine- a

chemical that stimulates

muscles in the airway to

contract.

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understand what causes of asthma and what

could be done to mitigate the root of this

disease. Although scientists today are still not

sure what causes asthma, a prevalent

hypothesis in the last decade suggests that good

hygiene especially in today’s health-conscious

society could be a potential cause. According to

a 2002 review published in Nature Immunology3,

scientists show clinical evidence suggesting that

children who are exposed to good commensal

bacteria early in life- the bacteria lost to good

hygiene- are less likely to develop asthma. The

bacterial exposure is thought to promote

immune tolerance to allergens- specifically by

suppressing the development of TH2 cells, and

by promoting the development of regulatory T

cells (Treg) to inhibit allergic inflammation in

asthma.

In support of the hygiene hypothesis, Dr.

Benjamin Marsland from the University Hospital

in Lausanne shows for the first time that the

mother’s commensal microbes can colonize the

lungs of neonatal mice. The bacterial

colonization of the lung, especially in the first 2

weeks of life, is crucial for suppressing asthma

later in life. In his paper published in the May

11th, 2014 online issue of Nature Medicine4,

Marsland suggests that factors influencing

microbial exposure early in life, including

antibiotic use or the mother’s diet, could have

implications on whether infants will develop

asthma.

In another study published in the May 20th, 2014

online issue of New England Journal of

Medicine5, Canadian researchers from McMaster

University show that antibodies suppressing

TLSP (thymic stromal lymphoid protein) could be

a potential treatment to combat the root of

asthma in human clinical trials. The clinical study

shows that TLSP is continuously produced in

individuals with asthma, and that TLSP-blocking

antibodies not only reduce baseline

inflammation in the lungs, but could also protect

asthma sufferers from developing an asthma

attack in response to inhaled allergens. The

study points to a potential treatment to combat

the root of asthma, and can be especially useful

for asthma suffers who may have become

tolerant to bronchodilators.

Overall, May 2014 marks two important

discoveries in asthma research, revealing the

neonatal origin of asthma early in life, and the

precise molecular mechanism behind the root of

the disease later in life. The discoveries can

point the way to early-life preventive strategies

and new treatments to combat the

immunological basis of asthma.

Preventing Asthma Early in Life- Mom’s

Microbes

One of the first things that newborns contact

during their early life in this world is their

mothers. Assailing the newborns is not only their

mothers’ scent, but also to their mother’s

microbes- commensal bacteria that colonize

various surfaces of the body including the skin,

the intestinal tract, the airway, and even the

lungs. While these microbes are initially thought

to simply provide protection against foreign

pathogens, a body of work suggests that

commensal bacteria can help orchestrate the

development of the immune system in

neonates6, and to shape the immune system in

adults7.

To learn more, read the full story in the June

2014 Issue…

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