2015 Johns Hopkins Nano-Bio Magazine

The Magazine of Johns Hopkins Institute for NanoBioTechnology | Winter 2015

Stem Cell Potential Training Across Disciplines

Nano Day!

Stem Cells in 3D!

A closer look

(full page research image and

caption)

Adipose-derived (that is, from fat tissue) stem cells sprout densely connected vascular networks when aggregated into multicellular spheroids prior to fibrin encapsulation.

Colors: CD31 (green), alpha-smooth muscle actin (red), laminin (blue). This image comes from the laboratory of Warren Grayson, assistant professor of biomedical engineering at the Johns Hopkins School of Medicine. (http://online.liebertpub.com/toc/tea/19/17-18)

CONTENTS Johns Hopkins University Institute for NanoBioTechnology Suite 100, Croft Hall 3400 North Charles Street Baltimore, MD 21218 Phone: (410) 516-5634 Fax: (410) 516-2355 http://inbt.jhu.edu Leadership Peter C. Searson DIRECTOR, REYNOLDS PROFESSOR

STORIES

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Stem Cell Advances Highlighted

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I Got My PhD...Now What?

Cells with Potential

at 2014 Symposium

Denis Wirtz VICE PROVOST FOR RESEARCH, ASSOCIATE DIRECTOR, SMOOT PROFESSOR

Staff Ashanti Edwards

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ACADEMIC PROGRAM MANAGER

Tom Fekete DIRECTOR OF CORPORATE PARTNERSHIPS

Boarding the Research Bandwagon

Ellie Boettinger-Heasley

Nanotech Knowledge Shared with Talented Youth

SENIOR ADMINISTRATIVE COORDINATOR

Gregg Nass SENIOR ADMINISTRATIVE MANAGER

Martin Rietveld DIRECTOR, WEB/ANIMATION

Mary Spiro SCIENCE WRITER

ADDITIONAL STORIES 2

Save the Date for Neuro-X

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Letter from the Directors

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Cross-disciplinary Facilities Expand

EDITOR, NANO-BIO MAGAZINE

Photography Lye Lin Lock Mary Spiro Michael Newman (NIST) Will Kirk of Homewood Photography Yi-an Lin Graphic Design Danielle Peterson BRIO DESIGN

ON THE COVER A visual approximation of scientists demonstrating the pluripotency of stem cells.

Illustration by Martin Rietveld

LETTER from the DIRECTORS Welcome to the Winter 2015 Nano-Bio Magazine and the ninth year for Johns Hopkins Institute for NanoBioTechnology (INBT) as a University research institute dedicated to creating new knowledge and new technologies to solve problems in health and medicine. Now more than ever, we find the tools that we have created with nanobiotechnology can offer our affiliated faculty and students unique opportunities to answer challenging questions in medicine, engineering and basic science.

This fifth edition of the Nano-Bio Magazine showcases some of the Institute’s leading edge research from talks given during our annual symposium, which focused on stem cell technology. You can also read about how our interdisciplinary pre-doctoral education programs have helped prepare our graduates for the job market. We also include a feature story about the Nano-Day for young scientists and engineers, which was coordinated by students from our labs.

Peter Searson

The future holds many new and exciting challenges for INBT researchers. We continue to work on solutions that will help diagnose and treat cancer. Questions about the blood-brain barrier remain a top priority for many researchers working in our affiliated laboratories. But we also are moving into new disciplines that we think have not been fully addressed using the tools of nanobiotechnology.

On May 2, 2015, we will hold our ninth annual symposium at the Johns Hopkins School of Medicine on the topic of neuroscience. We are calling this symposium Neuro-X, where the X indicates many disciplines in medicine, science, and engineering. Please save the date and join us then! In the meantime, we hope you enjoy this edition of Nano-Bio Magazine.

Peter Searson Director, INBT Denis Wirtz

Reynolds Professor, Materials Science and Engineering

Denis Wirtz Vice Provost for Research Associate Director, INBT Smoot Professor, Chemical and Biomolecular Engineering

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Johns Hopkins University Nano-Bio Magazine

PHOTO BY YI-AN LIN

Stem Cell Advances Highlighted at 2014 Symposium The annual symposium for Johns Hopkins Institute for NanoBioTechnology (INBT) was held May 2, 2014 in the Owens Auditorium on the Johns Hopkins School of Medicine Campus. The theme of the symposium was Stem Cell Science and Engineering and brought together six experts in the area of stem cell research and technology. Graduate student reporters from INBT affiliated laboratories prepared synopses of each presentation.

Linzaho Cheng—Human Cell Engineering: Recent Progress in Reprogramming Cell Fates and Editing the Nuclear Genome Linzaho Cheng is a founding member of the Stem Cell Program in the Johns Hopkins Institute for Cell Engineering and the Edythe Harris Lucas and Clara Lucas Lynn Chair in Hematology at Johns Hopkins Medicine. The driving goal for Cheng’s research reads like science fiction. Cheng and his team are working on understanding how stem cell manipulation could lead to a cure for genetic diseases.

This cure would follow a conceptually simple but technically challenging chain of events: differentiated somatic cells (that is, fully matured cells) would be collected from the patient, reprogrammed to become induced pluripotent stem cells (iPS cells), genetically engineered to fix the defect, differentiated to a specific cell type in which the defect manifested, and then transplanted back to the patient. With the genetic abnormality fixed, the patient would cease to experience symptoms of the disease.

The first three steps in this cure are becoming increasingly attainable. Specifically, Cheng described his team’s progress in generating and editing hematopoietic (blood-derived) stem cells. Because these cells are derived from blood cells, they can be routinely obtained. Cheng’s lab has done pioneering work on the reprogramming of somatic cells into iPS cells, demonstrating that a reprogramming method called

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episome-mediated reprogramming does not create mutations

These challenges drive the need for engineered bone grafts with

associated with cancer development. Furthermore, their work on

anatomical shapes and vigorous blood supply. If these goals can be

editing the genome of iPS cells using CRISPR/Cas9 nucleases

met, patients requiring facial bone grafts will have greatly improved

has shown that the CRISPR/Cas9 procedure is highly specific

outcomes.

and capable of changing a single DNA nucleotide or larger DNA

Warren Grayson is the director of the Laboratory for Craniofacial

segment. Cheng classified these steps as breakthroughs in genetic

and Orthopaedic Tissue Engineering in the Translational Tissue

engineering that can now be implemented even in labs without

Engineering Center at Johns Hopkins Medicine and Assistant

stem cell expertise.

Professor of Biomedical Engineering at Johns Hopkins University.

Ultimately, Cheng hopes to couple these reprogramming capa-

Grayson’s lab is working to engineer bone grafts that become

bilities with the generation of red blood cells and platelets from

incorporated into the blood vessel network of the patient and form

iPS cells for patients that are dependent on blood transfusions. For

intact bone and that are customizable and anatomically correct.

safety reasons, stem cells would most likely not be injected directly

He presented his exciting work on fat cell derived stem cells

for fear of differentiation into cancerous or other non-desirable

at the eighth annual symposium of the Johns Hopkins Institute

cells. Therefore, to complete the vision of a genetic cure, iPS cells

for NanoBioTechnology.

need to be differentiated into the desired cell type before engraft-

To accomplish this goal, the Grayson lab is using adipose-de-

ment in the body. Cheng’s lab has developed a strategy to produce

rived stem cells (ASCs), which are readily available from lipoaspi-

red blood cells from iPS cells in a bioreactor with 10 to 30 percent

rates (the material removed during lipsuction). These ASCs behave

differentiation efficiency. Ongoing work in the lab aims to increase

differentially than bone marrow-derived mesenchymal stem cells in

the efficiency of this process.

a manner that appears to promote blood vessel and bone formation.

Cheng’s presentation began with what he described as a “pro-

The population of ASCs obtained from a patient is heteroge-

vocative” statement—that animal models of human disease aren’t

neous, enhancing differentiation into cell types that form either

good enough, and that well-understood mouse models that have

blood vessels or bone. For example, ASCs expressing a surface

dominated the field for the past 30 years must be improved upon

protein called CD31 are responsible for growing blood vessels.

to advance human health. The take home message from his work,

Grayson and his team have demonstrated that when ASCs are

however, may be even more provocative. If physicians and engi-

treated with platelet-derived growth factor (PDGF), the generation

neers can control the genetic code of an individual’s cells, genetic

of blood networks is further increased. After vessels form, ASCs

diseases may one day be a thing of the past.

that have differentiated to bone forming cells lay down the mineral

—Colin Paul

building blocks of bone, using the vessels as a kind of template.

Therefore, ASCs that are properly treated with PDGF are capable Warren Grayson—Regenerating Musculoskeletal Tissues from Fat

of producing the precursors of healthy bone.

With this promising knowledge of the cues that ASCs need to develop, Grayson’s lab is now engineering a scaffold to deliver the

Each year hundreds of thousands of

cells and platelet-derived growth factor to the site of injury. By

medical procedures require bone grafts

using polycaprolactone, a biodegradable polymer, in a 3D printer,

to the skull. Traditionally, these grafts

Grayson’s team can construct anatomically correct scaffolds in

are performed by breaking up the

which ASCs can differentiate into vascularized bone. Using the 3D

fibula and trying to reconstruct the

printer, a scaffold in the shape of a jaw or nasal cavity can be made

bone structure of the skull.

to accommodate a patient’s specific injury.

Because the skull dictates facial features, this process is extremely

The scaffold is initially coated with a hydrogel amenable to cell

important to patient appearance and function. But the process of

growth. Following a period of cell growth and vascular differentia-

reconstruction comes with challenges. Imagine trying to build a

tion in the lab, these scaffolds can be implanted. Grayson’s lab has

human jaw from an inflexible cylinder.

already demonstrated that cells implanted in these scaffolds can

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Johns Hopkins University Nano-Bio Magazine

PHOTO BY YI-AN LIN

survive implantation into mice and maintain structural integrity,

Linda Resar—Hitting the

both in the scaffold and in the cell-formed structures formed

Bull’s Eye: Targeting HMGA1

within. Their work on scaffold engineering was recently published

in Stem Cells for Cancer Therapy

in the Journal of Biomedical Materials Research Part A.

or Regenerative Medicine

Grayson’s exciting work innovatively combines stem cell and

using Nanotechnology

biomedical engineering. They are now working to incorporate “oxygen tanks” into their scaffolds to increase oxygen transport to

Linda Resar is internationally recog-

the cells and further improve cell survival. These advances hold

nized for pioneering studies on the role

great promise for musculoskeletal regeneration from accessible and

of High Mobility Group A (HMGA)

abundant stem cell populations.

proteins in cancer. In 1992, she received an American Society of

—Colin Paul

Clinical Oncology Young Investigator Award and was recruited to the faculty of the Johns Hopkins University School of Medicine.

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Resar is board certified in Pediatric Hematology/Oncology and

It is critical to find methods that control this differentiation into

is an attending physician in the Hematology Clinic at the Johns

a desired specific cell type for the application of interest.

Interestingly, nanotechnology methods have shown great promise

Hopkins Hospital.

Resar’s research provides great promise for blocking progression

in overcoming these challenges. Specifically, combining topographical

of cancer. Her talk focused on a family of proteins termed “high

cues, such as engineered nanofibers, with biochemical growth factors

motility group A1.” These small proteins alter chromatin structure

can greatly increase efficiency of desired differentiation.

in the nucleus and thus regulate transcription of proteins.

A particular gene encoding for these proteins, HMGA1, is

Mao’s group has prepared electrospun fibrous scaffolds that highly resemble the body’s natural extracellular matrix. These scaffolds

enriched in stem cells of embryonic development as well as in

have proven successful in enhancing stem cell survival in addition

poorly differentiated cancers. In fact, the gene’s expression strongly

to directing specific stem cell fates. In another fascinating study,

correlates with poor prognosis in cancer. For instance, cancer

Mao collaborated with the laboratory of INBT affiliate Sharon

cells derived from the most metastatic cancers exhibit the highest

Gerecht, associate professor of chemical and biomolecular engi-

expression levels of HMGA1.

neering, in the development of a novel three-dimensional fibrin

Additionally, patients who relapse after cancer treatment tend to have high levels of the gene, and patients with the highest expres-

microfiber scaffold to engineer a small blood vessel. ~Allison Chambliss

sion levels have the lowest survival probability. HMGA1 also may drive a cancer stem cell phenotype. Consequently, there is hope

Mark Powers—Engineering Human

that targeting the gene may lead to the discovery of effective cancer

Pluripotent Stem Cells for Disease

therapeutics. In breast cancer cells, silencing the gene induced a more

Modeling and Applications:

normal breast cell phenotype and prevented metastatic progression.

Perspectives from a Tools Provider As Senior Director of Research and

Resar is currently working on an exciting collaboration with INBT affiliated professor Justin Hanes from the Johns Hopkins

Development for Cell Biology at

School of Medicine to develop a nanoparticle delivery method that

Thermo Fisher Scientific, Mark Powers

would block HMGA1 activity.

gave a vivid introduction about how

~Allison Chambliss

the R&D group in this top biotechnology company supports bioengineering research and society. His Hai-Quan Mao—Engineering

lecture showed the effort Powers’ research term made to develop

Biomaterials to Enhance

more reliable reagents, optimize the conditions, and help in hands-

Stem Cell Potential

on education and training for researchers.

Hai-Quan Mao is a professor

others to build a human induced pluripotent stem cell model of

of materials science and engineering

Parkinson’s disease (PD) in a dish to elucidate the molecular basis

at Johns Hopkins Whiting School

of PD and to identify compounds that impact disease phenotypes.

of Engineering and an INBT affiliated

They took fibroblast biopsies from the patients, derived iPSC lines

faculty member. He opened his talk

using Sendai viral vector, performed TALEN-based gene editing

Powers also gave an example of the company’s collaboration with

by explaining several of the biggest technical hurdles that often

and correction on alpha-synudein and LRRK2 genes, and then

prevent translation of stem cell-based therapies.

differentiated the iPSCs into neuron stem cells to measure the

One such obstacle is cell delivery. Implementing a stem cell therapy to a new source can have risks, and methods must be developed that increase cell survival while preventing inflammation and scar formation.

PD-related phenotype and the pharmacological rescue with known effective drugs.

All the key reagents and kits used in the experiments were from

Another major obstacle is the cell source. Stem cells are pluripotent,

the company’s own product catalog in order to stand in the cus-

meaning they have the capability to progress into several cell types.

tomer’s shoes to find any defects and make improvements. Powers

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Johns Hopkins University Nano-Bio Magazine

said he believed that by doing this his team would not only be able

Writers

to contribute their findings to the PD study, but also to take the

Allison Chambliss recently completed her PhD under Denis Wirtz

challenges and opportunities that occur along the entire workflow

in the Chemical and Biomolecular Engineering Department. She is

of pluripotent stem cell research and provide better products and

now a clinical chemistry postdoctoral fellow with the Department

service to customers.

of Pathology at the Johns Hopkins Hospital.

—Ying Wang Colin Paul is a fifth-year PhD student in the laboratory of Konstantinos Guo-li Ming—Understanding the function of risk genes

Konstantopoulos in the Department of Chemical and Biomolecular

for mental disorders using iPSC

Engineering and Institute for NanoBioTechnology. His thesis project

model

examines tumor cell migration in engineered microenvironments.

Guo-li Ming is currently a professor at

Ying Wang is currently a fifth-year PhD student in Sharon Gerecht’s

the Institute for Cell Engineering the

lab in the Chemical and Biomolecular Engineering Department,

Johns Hopkins School of Medicine.

co-advised by Dr. Linzhao Cheng in the Institute for Cell Engineering

Her work focuses on the mechanisms

in the Johns Hopkins School of Medicine.

of neurological diseases arising from aberrant neural development and circuitry formation.

Ming’s lecture detailed the courageous, ongoing research into schizophrenia, one of the most common and devastating psychiatric diseases with neural developmental origin affecting about 1 percent of the population in the U.S. She described their study in a familial mutation in Disrupted-In-Schizophrenia 1 (DISC1) gene locus, which is involved in multiple psychiatric disorders and cognitive disorders.

Four patients from the same family were studied who shared the unique four base pair deletion in the DISC1 locus and developed schizophrenia. Patients’ fibroblasts were reprogramed into iPSC lines.

All these cell lines showed a heterozygous mutation in one allele.

Using these iPSC lines, Ming’s group generated forebrain specific neural progenitor cells (NPCs)—cortical neuronal subtypes—that represented the phenotype of schizophrenia.

The results showed that the neural progenitor cells with the DISC1 mutation showed defects in the morphological development, decreased density of SV2+ synaptic boutons, defects in presynaptic vesicle release, and decreased glutamatergic synaptic transmission.

They also performed TALEN-induced gene correction and mutation correction, looking for the recovery of phenotype.

Based on the gene expression changes in disease cell lines, they found that many upregulated genes actually were proved to be involved in various mental disorders.. Ming said she hopes their studies of the mechanism of schizophrenia can shed light on potential therapeutic targets for correcting synaptic defects to cure schizophrenia.

—Ying Wang

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10 Johns Hopkins University Nano-Bio Magazine

I Got My PhD...

Now What?

BY ALLISON CHAMBLISS AND MARY SPIRO

On the National Science Foundation’s website, there is a definition

What could help a graduate student stand out among others

of interdisciplinary research; but there is also one caveat: “What is

is an interdisciplinary training background that spans multiple

considered interdisciplinary today might be considered disciplinary

scientific areas. Johns Hopkins Institute for NanoBioTechnology

tomorrow.” With this in mind, Johns Hopkins Institute for

paves the way for innovative ways to approach these challenges

NanoBioTechnology is at the forefront of interdisciplinary training

in graduate education. Students associated with INBT’s Nano-Bio

methods, creating a template to keep up with these continually

Graduate Training Programs are provided with a needed advantage

emerging new “fields” of study.

through interaction with cross-departmental co-advisors and re-

However, many universities still cling to a thesis-based graduate training model, which can be very topic-specific and prove to be limiting for new PhDs ready to get a jump on the job market.

search collaborators, as well as a slew of unique training courses in everything from laboratory techniques to communication.

Only a few extra courses beyond the departmental requirements

Doctoral students often spend five or more years deeply examin-

for a PhD are necessary to complete the Certificate of Advanced

ing a narrow research topic, only to find that companies and other

Study in Nanobiotechnology developed by INBT. They include

academic institutions are looking for scientists to work in vastly

two courses specific to nanobiotechnology, a course in advanced

different areas. Indeed, the true value of the doctorate degree is not

cell biology, a weekly journal club, nanobio tutorial workshops and

necessarily in becoming an expert in a specific research area, but

a course in communication. And the testimonies of the impact of

more in developing the logical and critical thinking skills and col-

this extra training from students who have been through the pro-

laborative attitudes required to succeed in any scientific field.

gram are powerful. Alumni and current students attest to the fact

Winter 2015 11

Angela Jimenez

that INBT’s interdisciplinary training both accelerates scientific

Craig Copeland

In the process, Angela has gained new knowledge that she

discovery and creates the most prepared and experienced scientific

wouldn’t have otherwise obtained from day-to-day experiences

researchers.

in the Wirtz Lab. “I was excited to learn about the dynamics of collaboration and how to work with people from different cultural

Collaboration offers discovery insight

and scientific backgrounds, as well as what types of projects are

Angela Jimenez, is a nano-bio training grant graduate student in

interesting and important to model mathematically.”

the lab of Denis Wirtz, professor in the Department of Chemical

What’s more, those perks won’t end once Angela finishes her

and Biomolecular Engineering and also vice provost for research

PhD. “All of these skills will benefit my career, regardless of what

for JHU. Angela is interested in measuring tumor growth in a

path I choose to pursue after I graduate,” she added.

novel three-dimensional cell culture system. Her experiments seek to define the relationship between invasiveness of cancer cells and

Journal clubbing into the job market

the dense collagen matrix that surrounds them, with hopes that

Kate Malachowski, a 2013 graduate of INBT from the lab of

this insight could potentially develop therapeutics to stop cancer

David Gracias, also an affiliated faculty member and professor in

from metastasizing.

the Department of Chemical and Biomolecular Engineering, has

But Angela’s experiments can only look at a few biological

seen first-hand how an interdisciplinary background can propel a

conditions out of hundreds of possible scenarios within the body.

career. Through INBT, Kate developed a collaborative relationship

Angela’s co-advisor, Sean Sun, an INBT affiliated faculty member

with Northrop Grumman, a large aerospace and defense contract-

and professor in the Department of Mechanical Engineering, has

ing company who provided her with a multi-year corporate spon-

helped Angela expand her experimental data into a mathematical

sored fellowship during her time as a Hopkins graduate student.

model that, with the input of a few parameters, could be valid to

INBT’s Director of Corporate Partnerships, Tom Fekete, facilitated

characterize cancer cell movement for any desired condition.

this fellowship.

“There are experiments that are not feasible except through

Kate’s fascinating project combined microfabrication and

modeling, so the collaboration helps us gain further insight into

engineering principles with medical expertise to create novel

what is going on within the tumors,” explained Angela.

“microgripper” surgical tools. She credits much of what she learned during her graduate years to INBT’s biweekly journal club.

12 Johns Hopkins University Nano-Bio Magazine

PHOTO BY MARY SPIRO; RIGHT: PHOTO BY MICHAEL NEWMAN (NIST)

Kate Malachowski

“Having the opportunity to meet biweekly allowed me to bounce

physics training, my biology/bio-engineering training, or both. In

ideas and brainstorm with peers who had diverse skill sets and

particular, when interviewing for my current position, I spent the

knowledge bases,” she said. Kate now works full-time at Northrop

day meeting with various members of the Center for Nanoscale

Grumman. Although her current work is based on the company’s

Science and Technology and found it surprisingly easy to talk sci-

electronics programs, she is eager to use her interdisciplinary knowledge

ence with folks working in a broad range of research areas.”

in order to introduce novel biological applications to these projects.

Craig also noted that interdisciplinary training provided valuable opportunities to learn things far beyond scientific facts from other

Broader understanding leads to better opportunities Students from disciplines outside of engineering are also attracted

areas of science.

“Not only the laboratory techniques required for biological

to the benefits of INBT’s multidisciplinary graduate training

work, but also problem solving techniques, teaching methodolo-

programs. Applicants for the Certificate of Advanced Study in

gies, and the simple broadening of my scientific vocabulary have

NanoBioTechnology come from several departments in the Krieger

all proved quite valuable to me; the latter especially with all the

School of Arts and Sciences, School of Medicine and even from the

attention that biological systems are currently getting,” he said. “I

Bloomberg School of Public Health.

believe that having an open mind and a flexible willingness to learn

In 2013 Craig Copeland earned his PhD in Physics in the laboratory of Daniel Reich, professor of Physics and Astronomy.

are valuable attributes for any professional, and my INBT training allowed me to gain experience putting these qualities to work.

He is now a postdoctoral researcher at the National Institute for Standards and Technology Center for Nanoscale Science and

Allison Chambliss recently completed her PhD under Denis Wirtz in

Technology. Craig is developing optical microscopes and methods

the Chemical and Biomolecular Engineering Department. She is now

for tracking nanoparticles as indicators of the motion of microme-

a clinical chemistry postdoctoral fellow with the Department of Pathol-

chanical and nanomechanical devices.

ogy at the Johns Hopkins Hospital.

“My interdisciplinary education has certainly been an asset moving beyond graduate school,” Craig said. “I was quite comfort-

Mary Spiro is INBT’s science writer and media relations director.

able looking for positions that required experience from either my

PHOTO BY WILL KIRK

Winter 2015 13

Adipose (fat tissue)-derived stem cells undergo vascular morphogenesis when seeded at high density and in the presence of angiogenic factors.Vessels express CD31 (green) and are surrounded by pericyte-like cells expressing alpha-smooth muscle actin (red). Nuclei are counterstained with DAPI (blue).

This photo was created by Warren Grayson laboratory, assistant professor of biomedical engineering at the Johns Hopkins School of Medicine. (http://online.liebertpub.com/toc/tea/18/15-16)

Cells with Potential

BY REZINA SIDDIQUE

Stem cells, cells in the body that can develop into practically any

and the Lucas and Lynn Chair in Hematology. Cheng has been at

tissue or organ, have been heralded for their potential therapeutic

the forefront of stem cell technology for more than 20 years, and

qualities to treat disease, but they are rare and difficult to expand.

can shed light on the history of stem cell medicine at Johns Hopkins.

Human embryonic stem cells that are made from early embryos,

In 1991, Cheng received his Ph.D. in Molecular Biology and

full of potential (called pluripotent) and able to expand in the labo-

Genetics from the Johns Hopkins School of Medicine, where he

ratory, however, carry some scientific as well as ethical concerns.

worked on human DNA replication models and transcriptional

In 2006, a group in Japan developed a method to generate what

factors, including one of the first two DNA-binding proteins from

are called “induced pluripotent” stem cells (iPSCs) using mouse skin

mammalian cells (NF-I/CTF), and published landmark papers in

cells. Before long, these engineered stem cells were being created by

Cell and PNAS. The young researcher was drawn to the emerging

genetically modifying human adult skin or blood cells. They also

field of stem cell technology.

exhibited exhibit the same qualities as embryonic stem cells.

Johns Hopkins University researchers have a long history of con-

Before joining the Johns Hopkins faculty, he was exposed to the challenges of researching stem cells in industry and in NIH.

tributions to stem cell technology. One of the university’s leaders

Cheng’s stem cell research career started as a postdoctoral fellow

in the field is Linzhao Cheng, professor of Medicine and Oncology

helping to establish the mouse pluripotent stem cell lines from pri-

and a founding member of the Stem Cell Biology Program at the

mordial germ cells, which was published in Nature in 1992. Since

Johns Hopkins Institute for Cell Engineering. He is also the As-

1994, his research has focused on human stem cell biology and

sociate Director for Basic Research in the Division of Hematology

cell engineering after he joined a pioneering stem cell company.

14 Johns Hopkins University Nano-Bio Magazine

However, one of the issues with these types of cells

Cheng joined the Johns Hopkins faculty in 1999 and received the Presidential Early Career Award for Sci-

is something called epigenetic memory, which means

entists and Engineers in 2003. In 2012, Dr. Cheng

that genetic information outside of the DNA strand

was elected as a Fellow of the American

persists. This can affect how the genes within the

Association for the Advancement of Sciences (AAAS).

DNA are expressed in future cultures of these cells.

These epigenetic memories can be negative or they can

Cheng says his early work in stem cells helped to cement his perspective that, “Good science should

also be positive but become particularly relevant in

not only be beautiful, but also useful.” He learned

cloning studies.

to approach science with the mindset of using it as a

In Cheng’s stem cell laboratory, the focus is on

tool to solve real world problems. In his lab, Cheng

blood disease modeling and its treatment. They use induced pluripotent blood stem cells to develop appli-

believes in integrated versus discrete research, and has a multidisciplinary team consisting of both biologists and

cations for blood disease. Fortunately for Cheng and his colleagues,

engineers, including a PhD student Ying Wang who is from

blood cells have a fairly low rate of mutation as compared to cell

Department of Chemical and Biomolecular Engineering.

types exposed to sunlight and environmental toxins. There is also a

In 2002, Cheng helped found the Johns Hopkins’ Stem Cell Biology Program in the then newly formed Institute for Cell Engineering. The program has two goals: first to understand how stem

relatively unlimited supply of blood cells from the patient or their best match.

The precise genetic engineering used to create iPSCs allows for

cells work and second, to find ways to use stem cells as tools to treat

tailored disease modeling and drug screening. Where previously

human disorders. But before long, he realized that working with

animal models were used and researchers tried to focus on the simi-

human stem cells was a lengthy process. To avoid the ethical, regu-

larities instead of the differences, induced pluripotent stem cells

latory, and practical constraints involved with using human em-

from blood allow for more elaborate and precise modeling using

bryonic stem cells, researchers were beginning to seek alternatives.

human cells to study humans, Cheng explained.

Then in 2006, researcher Shinya Yamanaka at Kyoto University in

Despite their advantages, using induced stem cells is not without

Japan developed the first “induced” pluripotent stem cells (iPSCs).

challenge, Cheng said. “For example, even induced stem cells can

Yamanaka later won the Nobel Prize for Physiology or Medicine

have complications comparable to adult human stem cells. For

in 2012 for his stem cell discoveries.

example, iPSCs as well as embryonic stem cells can form teratoma

Induced means that cells that are not originally stem cells, but other tissue cells, are genetically modified to behave like stem cells.

(a benign tumor composed of multiple tissue types generated from pluripotent cells),” he said.

Induced pluripotent stem cells can be developed from adult cells by

In the short term, such complications may shift in the way

introducing a set of genes into a particular cell type. As pluripotent

research on disease and drug testing is performed with induced

stem cells, they have the powerful ability to propagate indefinitely

stem cells. But in the long term, iPSC-based research can lead to

and can be induced to become any other type cell in the body:

regenerative therapies, such as cell transplantation and transfusion.

from to blood to neurons to tissue.

The Cheng lab is actively working on generating large numbers

Cheng recalls attending a lecture where induced pluripotent stem

of red blood cells from human iPSCs in the laboratory. This may

cells were first discussed. “They described inducing pluripotency as

provide a new solution for transfusion-dependent patients who

essentially reversing the biological clock of a cell within a test tube,” he said.

developed immune rejection to a donor’s red blood cells and lack

The procedure of introducing the pluripotency genes was first

other alternatives for obtaining needed red blood cells. Through an

performed successfully in mice, followed by humans, as is often

integrated, multidisciplinary approach, Cheng said, he expects the

the case with biological research. Using only a few drops of human

induced pluripotent stem cell technologies to have a bright future

blood, scientists were able to create stem cells nearly identical to

with many potential therapeutic applications.

embryonic stem cells.

Rezina Siddique earned her Ph.D. in biomedical engineering at Johns Hopkins University.

Winter 2015 15

Cross-disciplinary Facilities Expand

BY MARY SPIRO

Croft Hall on the Homewood campus houses the headquarters for

Hristova and Martin Ulmschneider from Materials Science and

Johns Hopkins Institute for NanoBioTechnology. INBT offices

Engineering; and Feilim Mac Gabhann from Biomedical Engineer-

and laboratories have occupied most of the building except for the

ing and the Institute for Computational Medicine.

second floor, which, up until a couple of months ago, had been

Along with lab and office space, there will be an imaging core

used for offices in the computer science department. Now INBT

composed of a suite of specialty microscopes managed by the

is set to expand once more to create a highly interdisciplinary and

Integrated Imaging Center (IIC) led by Michael McCaffery, whose

flexible environment for nanobio research.

main facilities are located in Dunning Hall on the Homewood campus. Student office space and gather-

In total, the renovation creates a little more than 12,500 square feet of space for INBT use in both Croft and Shaffer Halls.

ing areas are also part of the plans. In total, the renovation creates a little more than 12,500 square feet of space for INBT use in both Croft and Shaffer Halls.

“This expansion will establish a vibrant community for nanobiotechnology

By the fall of 2015, new facilities for a group of INBT affiliated faculty members will open on the second floor of Croft Hall and also encompass part of Shaffer Hall. The new space allows INBT

research and education for INBT affiliated faculty, students and staff,” said INBT director Peter Searson.

The faculty members involved in the expansion all have primary

to continue as a model for integrated research and education at

lab and office space in their respective departments, noted Searson.

Johns Hopkins, and will further enhance INBT’s reputation and

But by providing these researchers with secondary laboratory

visibility. The expansion includes laboratory space for two faculty

spaces, Searson added, “we will be able to leverage their comple-

members from the Johns Hopkins School of Medicine, Martin

mentary expertise and further our commitment to interdisciplinary

Pomper, MD, PhD from Radiology and Oncology and Laura

research, as well as generate new resources for the Whiting School

Wood, MD, PhD from Pathology and Oncology, both of whom

of Engineering and the University as a whole.”

are contributing to ongoing INBT programs. In addition, INBT will house laboratory space for five engineering faculty including Sean Sun and Jeff Wang from Mechanical Engineering; Kalina

16 Johns Hopkins University Nano-Bio Magazine

Watch the INBT blog for updates on the renovations as they occur at this link http://inbt.jhu.edu/blog.

Boarding the Research Bandwagon

BY PRANAY TYLE

Pranay Tyle (left) credits his laboratory mentor Hasini Jayatilaka as being a key to his undergraduate research success.

PHOTO BY MARY SPIRO

Winter 2015 17

The story of how I joined Johns Hopkins Institute for NanoBio-

The best part of being involved in research, apart from the work

Technology (INBT) is actually one of those moments where it

you do, is sitting in class in a lecture hall and suddenly tune in to

just hits you – Why haven’t I thought about doing this before?

the professor talking about something that you do in lab each day.

It started with me being back at home during the winter of my

That moment cements your understanding of why you did what

sophomore year, meeting friends of my parents and answering the

you’ve been doing for so many days, it connects the dots in your

most common question: Where do you study? One of the reactions

mind, and that moment is when you’ve completed the full circle

that stuck with me the whole night was “Wow, how does it feel to

between theory and practice.

be in the center of the most cutting-edge research?” This made me

For me personally, having to come to lab got me into a disci-

realize how I’d been oblivious to one of the things I would love to

plined schedule. I had a fixed time for all days of the week now to

get involved in.

wake up (which for me used to be the latest possible time), since if

Better one and a half years late than never, I decided to join the

I had no morning classes, I was in lab. It helped me a lot with my

research bandwagon as well. I started going through the profiles of

time management skills, with me cutting down on TV shows and

labs on Homewood campus, looking for a topic that would make

sporadic naps. To my surprise, it did not affect the amount of time

me want to be there in lab every free minute during the year. I

I spent with my friends, as the reduction in TV shows and naps

finally found one that sparked my curiosity: the Denis Wirtz Lab.

was (extremely) disturbingly enough to keep every other aspect of

Dr. Wirtz is the Smoot Professor in the Department of Chemi-

my daily schedule the same. Being surrounded in lab by people in

cal and Biomolecular Engineering and also the University’s Vice

similar academic disciplines also gets me a ton of advice on classes.

Provost for Research.

It’s like my own little “rate-my-professor” that encourages me to

Though at the time most of the stuff I read about the Wirtz lab

definitely take some class if it is “the best class I will take at Hop-

went over my head, I knew that cancer was something I had always

kins”. At times, it’s also a ‘learning den’ where I can get help with

wanted the world to be rid of. Seeing near and dear ones succumb

classes if I need to. Getting involved in a research lab also came

to it was one of the most excruciating things which I wanted no

with social outings with the team, with our dinners enabling us to

one to experience in the future. Fascinated by the approach taken

get to know each other on a more personal level. I feel that this in a

by Dr. Wirtz, I shot him off an email and to my amazement, I got

big way contributed to the chemistry we have while working with

an email back within the hour, “Sent to my grad students, look

each other, made us comfortable spending time with each other at

forward to working with you.” The next day I was scheduled to be

work.

back in Baltimore, and the day after that, I was a part of Wirtz lab.

During my training, I remember asking one of my peers “How

At this point, after nine exciting months, including a fully lab-packed summer, I feel that this continues to be one of the

in the world can I remember all these procedures, let alone do

best decisions I made so far. I do not regret being here every day,

them?” She simply smiled and said, “You’ll see.” In a few weeks, I

but take pride in saying “I need to be in lab.” One of the most

found myself doing those very procedures, one step after another as

cherished take-away for me is developing a sense of accountability

if it were a reflex action. I would most definitely attribute me being

for my actions, which I feel is an important aspect in life. I would

able to do this to my grad student Hasini Jayatilaka. At the end of

definitely encourage being involved in research while at Hopkins as

the day, what I felt it boiled down to, was realizing that the person

you have nothing to lose but so much to gain.

I work for was in the same shoes five-seven years ago as I was now, and she wouldn’t expect anything unrealistic out of me. Once you

Pranay Tyle, is a junior in Chemical and Biomolecular Engineering

embrace the challenge ahead, knowing that there is no need to be

minoring in Economics, and hopes to one day manufacture low cost

intimidated, you’re good to go.

medicine accessible to those in dire need across the globe.

18 Johns Hopkins University Nano-Bio Magazine

Assistant Professor Chao Wang demonstrates renewable energy project.

Nanotech Knowledge Shared with Talented Youth

BY MARY SPIRO

PHOTO BY LYE LIN LOCK

Winter 2015 19

Plant-based solar cells.

Assistant Professor Honggang Cui helps a CTY student in nano-drug delivery project.

One way to encourage more kids to be interested in science and

“This clinically relevant experiment demonstrated how some

engineering is to offer them fun ways to learn about it. Johns

chemotherapy drugs need an extra ingredient to make them more

Hopkins Center for Talented Youth creates such opportunities

soluble, and therefore, more effective in treating cancer.” Zhang

throughout the year. Students and postdoctoral fellows from Johns

said. “Many cancer drugs have poor solubility and this is a big issue

Hopkins Institute for NanoBioTechnology-affiliated laboratories

for biomedical applications. Since many molecules do not dissolve

recently had the chance to help budding young scientists and engi-

very well, we have to use a carrier, in this case a surfactant, to make

neers by developing hands-on projects for CTY’s nanotech day.

them dissolve. We used a model molecule that is similar to a cancer

The event, “Small is Big: Using Nano-Sized Objects to Address

drug and compared how well the molecules dissolved with and

Global Problems,” offered five different nano-related projects for

without the surfactant. With the surfactant, it remained stable and

middle school aged children (and their curious parents) to try

in solution much longer.”

out. Project leaders came from the laboratories of professor David

Zhang said a clear color change associated with the experiment

Gracias, and assistant professors Honggang Cui and Chao Wang

made it easier to mark results. If the molecule did not dissolve, the

from the Department of Chemical and Biomolecular Engineering;

particles remained bright yellow. If the molecules dissolved, the

Michael McCaffery, director of the Integrated Imaging Center;

solution became bright green.

and Beverly Wendland, professor of Biology and acting dean of

“The kids were not really familiar with basic science, so you had

the Krieger School of Arts and Sciences. Project topics included

to tell them everything from the beginning,” said Ran Lin, one of

designing nanomedicines, nano-enabled renewable energy, micro-

Cui’s predoctoral students who helped lead the project. “But they

and nano-patterning, using fluorescence in biological imaging and

were really curious. Some of the parents were even more curious

Mendelian genetics. Groups of students and their parents rotated

about the projects because they had had experience working in

through each project that was set up in various locations on the

laboratories.” Another graduate student from the Cui lab who

Homewood campus.

helped present the experiment to the students, Lye Lin Lock, took

The project on nanomedicine from the Cui lab, which was

photos throughout the day (shown here).

developed by postdoctoral fellow Pengcheng Zhang, used a simple chemistry experiment to drive home its message.

20 Johns Hopkins University Nano-Bio Magazine

PHOTOS BY LYE LIN LOCK

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