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nstitute of I iotechnology B

Biotech Pl a z a

FRONTIER BIOTECH from Finland


Biotech Pl a z a

Table of contents Mission Statement

2–3

Institute Overview 4–5 Introduction – Target Areas HEALTH AND DISEASE

6–7 10–15

NEURODEGENERATION 18–25 SMALL MOLECULE PHARMA

28–39

CELL AND PROTEIN TECHNOLOGIES

42–57

BIG DATA

60–67

PLANTS AND FOOD

70–79


BI is Finland’s flagship institute for molecular biosciences, home to more than 250 researchers from all over the world. Our scientists are at the international forefront of research in genomics, structural biology, bioinformatics, molecular neuroscience, cell and developmental biology and plant sciences. BI’s main focus is basic science, but we also seek to commercialize our research findings, for society’s benefit. This prospectus is the launch document for Biotech Plaza. It is aimed at potential investors, academic and industrial partners, funding agencies, business developers, end-users and any other types of stakeholder, whom we invite to join with us to turn our dreams into reality.

Howy Jacobs Institute Director

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Here we set out a range of projects in progress, with strong commercial potential. Some are broad, others narrowly focused. Some are already close to being realized, whilst others are long-term and aspirational. Some are aimed at well-defined niche markets, whereas others seek to establish technologies to tackle globally important problems. All of them have arisen directly from BI’s discovery science. But to develop them will require different kinds of support and expertise than our scientists can provide on their own. Biotech Plaza brings together a wide spectrum of advisors, actors and financing tools to accomplish this task, with a strong emphasis on the global marketplace. Meanwhile, our research teams continue to replenish the discovery pipeline.

Troy Faithfull Development Manager, Biotech Plaza

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bi.helsinki.fi

an independent institute of the University of Helsinki

Global

Innovation

BI is Finland’s flagship institute for molecular biosciences, home to

BI’s future innovation potential includes studies of pathogen

more than 250 researchers from all over the world. With a culture

resistance in cereal crops, structural analyses of complex viruses

of excellence and a strong track-record of success, it nurtures

like measles, targeting RNA and RNA metabolism as therapies for

discovery, technology, careers and businesses.

cancer and neurodegeneration, unraveling the genetic circuitry controlling organ formation, computational tools to interpret the

Cutting-edge Our scientists are at the international forefront of research in genomics, structural biology, bioinformatics, molecular

massive data sets emerging from genome analysis, and screens for molecules capable of blocking substrate-specific protein secretion.

neuroscience, cell and developmental biology and plant sciences.

Investment

Our main focus is basic science but, in addition, we vigorously

BI seeks partnerships from the private sector, in order to develop

pursue commercialization of our research findings.

and commercialize its inventions. World-class discovery science, combined with Finland’s transparent business environment and

Technology Current projects with major potential impact include a revolutionary

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highly skilled workforce, are ingredients for commercial success.

technology for treating killer diseases caused by defects in the cell’s

Opportunity

energy system; new drugs to reverse the nerve damage that causes

Investors and supporters can become stakeholders in BI as a

neurodegenerative diseases, and protein engineering tools based

whole, in specific projects or in startups to be established jointly.

on the splicing activities of inteins.

Contact us to explore possibilities.


BI

established

1989

in numbers

145

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applied patents

bioscience technologies established in Finland

10

startups

>250 doctoral theses

25

research grants in excess of $1 million

300 ~ publications in top-ranked international journals

Contact us to explore possibilities at

biotechplaza.org

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Biotech Plaza showcases the innovative technologies arising from BI’s scientific work at the frontiers of biological knowledge. We are looking for partnerships and financing to turn our ideas into products and services that will have major societal impact.

Health and Disease

Neurodegeneration

Small molecule pharma

Many of the world’s most intractable

Age-associated neurodegenerative diseases

The search for new and better drugs for

diseases arise from disrupted intracellular

are currently incurable, and impose a

use in the personalized therapies of the

communication or homeostasis. Our

massive societal and economic burden, as

future is one of the major drivers of today’s

scientists are working on novel technologies

well as individual suffering on a colossal scale.

pharmaceutical sector. This involves not just

to alleviate damage arising from deranged

Many labs around the world are working

the identification of more specific targets but

cell signaling, focusing on key regulatory

to understand the underlying pathological

the implementation of ‘designer’ screening

pathways affecting proteotoxicity in the

mechanisms as a route to therapy. We have

platforms. Biotech Plaza features BI’s ongoing

endoplasmic reticulum, oxidative stress in

prioritized ‘out-of-the-box’ approaches,

work to create more specific anticancer

mitochondria, and interactions between

based on novel strategies to activate

drugs, immune modulators, antibiotics,

the cell nucleus and cytoplasm. BI aims to

natural, neuroprotective, stress-handling

and agents directed at new targets in

produce breakthrough treatments for a huge

mechanisms. We believe our new concepts,

neurodegenerative and viral diseases. This

spectrum of pathological states, ranging

presented here, will bring concrete and

builds on our strong profile in structural and

from septic shock, to inherited heart disease,

dramatic benefits to the treatment of stroke,

cellular biology.

diabetes and cancer.

movement disorders and dementia within the next decade.

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Target areas of Research Projects

Cell and protein technologies

Big data

Plants and Food

The new science of genomics has been made

Modern genetics opens up enormous

Future medicine will be based upon strategies

possible not only by the orders-of-magnitude

possibilities for altering the properties of

for tissue repair and regeneration, and the

advances in DNA sequencing and the equally

crop plants, to address the major global

delivery of exquisitely targeted therapeutic

astonishing decrease in its costs, but also

challenges of our time: climate change,

drugs and proteins with minimal side-effects.

by the development of data-handling and

resource depletion, pollution, and hunger.

Biotech Plaza presents a wide spectrum of

pattern-recognition tools that enable us to

We are focusing on improved pest-resistance

new technologies and discovery science to

make sense of the vast amounts of data

in cereal crops, enhancing the rate of carbon

enable these goals, ranging from new systems

from biological and clinical specimens that

capture in sustainable forests, modifying

to engineer proteins and drug-conjugates, to

DNA sequencing generates. BI’s research

trees so as to produce more suitable raw

the elucidation of the molecular mechanisms

teams are at the forefront of developing and

materials for the chemical and biofuel

whereby stem cells stay young and retain

applying computational methods to make

industries, and a more efficient way to

regenerative capacity. We are also developing

sense of big data emerging from genomic

engineer targeted gene modifications in

services for customized gene expression

analyses, and using it to predict the safety

common crop plants.

and manipulation to serve the research

of nanomaterials, the hazards of post-

community, and novel reporter systems to

operative infections or to serve the needs

profile pathological disturbances in cellular

of conservation biology, environmental

growth status and in subcellular protein

management and agriculture.

localization.

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Health & Disease

The Alternative Oxidase AOX – a revolutionary tool for wide-spectrum therapy | Howy Jacobs MANF as a novel therapeutic target for the treatment of diabetes | Maria Lindahl Mitochondrial membrane proteins – structure and function in health and sickness | Vivek Sharma

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Howy Jacobs

The Alternative Oxidase AOX – a revolutionary tool for wide-spectrum therapy We are developing a revolutionary therapy for diseases caused by malfunction of the mitochondria, the energy plants of our cells. We take advantage of a natural system found in lower organisms for resisting mitochondrial stresses. By deploying this system in humans, we hope to treat a wide spectrum of currently incurable and fatal diseases, whether caused by environmental poisons, inherited mutations, metabolic overload or damage due to ‘wear and tear’ during aging.

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Mitochondria recover the primary chemical

Mitochondrial dysfunction causes many

power up properly, when the oxygen supply

energy released from the breakdown of

fatal conditions, including rare, multi-system

is transiently interrupted. The inflammatory

food molecules in forms that the cell can

diseases of infancy, as well as degenerative

processes leading to chronic lung diseases

use. This enables vital processes such as

disorders of old age. Major killers such as

are initiated by specific poisons in toxic

muscle contraction, electrical conduction

heart attack and stroke result from the

smoke that disable the mitochondria and

between nerve cells and hormone secretion.

inability of mitochondria to shut down and

prevent the efficient clearance of particulates.


Our strategy is to supply AOX … to combat mitochondrial damage

And fatal multiple organ failure in sepsis has

it is blocked, maintaining cellular functions,

been attributed to mitochondrial shutdown.

preventing the build-up of toxic oxygen radicals, minimizing the disruption of normal

• a key indicator of physiological stress following cardiac infarct, and • neurodegeneration seen in models of

Our novel, therapeutic approach employs

metabolism and preventing cell death. We

the alternative oxidase, AOX. AOX by-passes

have shown that transgenic rodents, flies or

the major energy supply pathway when

mammalian cells endowed with the AOX gene

AOX thus has immense and broad potential

transplanted from a marine invertebrate are

in medicine, ranging from a treatment

protected from many pathological insults that

for rare diseases to the protection of

affect mitochondria in humans, including:

populations at risk from biohazardous

• inherited mitochondrial mutations causing

agents. Our strategy is to supply AOX (using

fatal infantile disease • the toxicity of cyanide or the cocktail of poisons in vehicle exhaust or cigarette smoke

Parkinson’s and Alzheimer’s diseases

viral vectors, mRNA-mimetics or as protein via cell-permeating peptides) to combat mitochondrial damage.

• multiple organ failure due to bacterial sepsis

Our immediate aim is to develop partnerships with others in the field of genetic therapy. We will develop ways of delivering AOX safely and effectively to affected tissues and organs, starting with life-threatening conditions where we have solid data from animal trials. End-users of our technology will initially be in the pharmaceutical sector, but it should also be applicable to protection of military personnel, civilian first-responders and populations at risk from terrorism or pollution.

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Maria Lindahl

MANF as a novel therapeutic target for the treatment of diabetes We have identified a new growth factor for pancreatic insulin-producing β-cells. In the future, it could be used to regenerate the lost β-cell mass in diabetic patients. This would restore normal metabolic control and avoid the severe, life-threatening complications resulting from diabetes. Collaborator: Mart Saarma

Diabetes mellitus is a group of metabolic

symptoms. Their administration does not

-cells from stress, as well as activate their

disorders characterized by hyperglycemia, in

faithfully mirror the physiological response of

regeneration. Various nutrients, hormones

turn caused by the inability of the endocrine

β-cells and does not prevent the devastating

and growth factors are known to affect β -cell

pancreas to maintain sufficient levels of

micro- and macrovascular complications

proliferation, but their use as therapeutic

circulating insulin. Type 1 diabetes (T1D)

of the disease. The reasons for β-cell

factors has remained minimal, because of

results from the autoimmune destruction

destruction both in T1D and T2D are still

lack of specificity. Therefore there is a need

of insulin-producing β-cells, leading to total

unclear, but increasing evidence implicates

for new and more specific targets for pre-

insulin deficiency, whereas type 2 diabetes

endoplasmic reticulum (ER) stress as a key

clinical screening and eventual clinical testing.

(T2D) develops when the β-cells are no longer

mechanism, accompanied by prolonged

able to respond to an increased insulin

activation of the signaling pathway linked to

Mesencephalic astrocyte-derived

demand due to insulin resistance. Today

the unfolded protein response (UPR). In turn,

neurotrophic factor (MANF) was originally

more than 380 million people are affected

this arrests protein translation and activates

identified as a secreted trophic factor for

by the disease, and its prevalence is rapidly

protein refolding and degradation.

dopaminergic neurons in vitro. MANF and

increasing.

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its homologue CDNF, discovered by our Thus, one of the main strategies for

group, can protect and repair neurons

Current medications, insulin and anti-diabetic

improving diabetes therapy is to define

and cardiomyocytes in animal disease

drugs, are able only to alleviate diabetic

and validate novel approaches to protect β

models. The protective role of MANF has


PhD Student: Tatiana Danilova

been suggested to depend on its ability to

combine MANF transgenic mouse lines and

rescue cells from ER stress. To understand

animal models for both T1D and T2D, as

its physiological role in vivo, we generated

well as cell-lines and organ culture. Other

MANF knockout (KO) mice that developed

potential approaches will also be investigated

severe insulin-dependent diabetes due to

for using MANF as a regenerative protein for

progressive loss of pancreatic β-cells. One

β-cells in diabetes.

of the underlying mechanisms was chronic ER stress. We found that recombinant MANF protein enhanced β-cell proliferation in cultured adult mouse islets, whilst pancreatic MANF overexpression in a mouse T1D model increased β -cell proliferation and prevented cell death. MANF is therefore a promising new therapeutic candidate for β -cell protection and regeneration. Our ongoing studies

Background photo: Jari Rossi and Ömer Acar

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Vivek Sharma

Mitochondrial membrane proteins – structure and function in health and sickness The main focus of our research is to understand how enzymes involved in ATP generation (respiratory enzymes) function at a molecular level, and how point mutations cause them to malfunction, giving rise to a range of serious disorders. For this purpose, we apply state-of-the-art computational methods on the available structural data, and explore spatial and temporal scales that are not easily reachable within the current experimental framework. Overall, our aim is to shed light on the molecular mechanisms of enzyme action, and use this knowledge to design possible remedies to combat pathological dysfunction.

Life on earth is powered by ATP, which

We have performed large-scale atomistic

achieved by microscopic gating elements,

is produced primarily in mitochondria

molecular dynamics simulations and high-

such as conformational dynamics of amino

as a result of electron transfer reactions

level quantum chemical calculations on

acid side chains and mobile water molecules.

that are coupled to proton translocation

respiratory complex I, which is the first entry

Here, our work strengthens the view that

across the inner-mitochondrial membrane.

point for electrons and one of the largest

evolution has led to optimal nanostructures

These elementary reactions (electron and

enzymes in the respiratory chain. Our results

that very efficiently convert energy from one

proton transfers) involve charged species,

show that both electrostatics and long-range

form to another.

and are efficiently performed by enzymes

conformational transitions play a key role in

embedded in a low-dielectric medium, i.e.

enzyme function, coupling the redox reaction

We envisage two key areas where our

the membrane. Malfunction in one or many

to proton pumping as far as 200 Ă… away from

research will have profound impacts; a)

intermediate steps of the catalytic cycle of

the former. Our work provides one of the first

mitochondrial medicine, and b) bioenergy. By

these enzymes leads to various metabolic,

molecular insights into complex I function,

studying molecular structures of intermediate

neurodegenerative and mitochondrial

and moves a step closer to identifying

states in the catalytic cycle of mitochondrial

disorders. Moreover, under environmental

the underlying causes of mitochondrial

enzymes the underlying molecular causes of

stress conditions these enzymes produce

dysfunction.

diseases can be identified. Second, a deeper

excess reactive oxygen species (ROS), which

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understanding of the molecular mechanism

are harmful to other cellular components, and

By performing long timescale fully-atomistic

of respiratory enzymes has enormous

lead to various mitochondrial disorders. It is

classical molecular dynamics simulations on

potential in the design and development of

of the utmost importance to understand how

complex IV of the respiratory chain, we have

biofuel cells of high efficiency.

these ROS are produced, and how that can be

shown how the enzyme manages to pump

contained to normal physiological levels.

protons with high efficiency (~90%). This is


A deeper understanding of the molecular mechanism of respiratory enzymes has enormous potential in the design and development of biofuel cells of high efficiency. 17


Neurodegeneration

Rejuvenating the brain: new strategies for neuroregeneration | Mikko Airavaara and Andrii Domanskyi A novel approach to treating Parkinson’s disease | Jaan-Olle Andressoo Targeting RNA toxicity in degenerative disorders | Susana Garcia Synaptic adhesion molecules - making neuronal connections to combat cognitive disorders | Tommi Kajander

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Mikko Airavaara & Andrii Domanskyi

Rejuvenating the brain: new strategies for neuroregeneration A viable strategy to treat neurodegeneration requires a toolbox for restoring neuronal networks in the damaged or aging brain. Using a unique set of in vivo and in vitro models and tools, we are developing a broad experimental approach to achieving this goal, focusing on two of the commonest such disorders, ischemic stroke and Parkinson’s disease. We use cutting-edge in vivo rodent models, combined with virus- and CRISPR-Cas9-mediated transgenesis, plus surgical and toxicological procedures, to evaluate novel drugs, neurotrophic factors, and non-coding RNAs with neuroprotective and neurorestorative potential. Using cultured primary cells isolated from embryonic and adult brain, we also investigate pathways regulating proliferation, migration and differentiation of neural stem cells and astrocytes, in order to assess the ways these cells could be used for rejuvenation of degenerating neuronal networks.

Aging increases the incidence of

line-Derived Neurotrophic Factor (GDNF)

fibril-induced or genetically engineered

neurodegenerative diseases and stroke,

and its family members promote survival of

rodent models. Applying a broad array of

leading to severe deficits in life quality.

neurons during development and disease. We

behavioral tests we have demonstrated the

Our ultimate goal is to increase the

are working with these factors, studying their

neuroprotective potential of CDNF and MANF

quality of life for the elderly, by preventing

interplay, mechanism of action, regulation

in these models, and have recently found

neurodegeneration and promoting neuronal

by microRNAs and their target genes, in

that stimulation of the microRNA biogenesis

regeneration. Neuronal loss is caused

protecting neurons against stress. These will

pathway promotes survival of cultured

by various stressors and by the aging

lead to novel treatment strategies to combat

dopaminergic neurons. We are currently

process itself. Current drug therapies

neurodegeneration.

testing the efficacy of selected microRNAs and

for neurodegeneration are still based on

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drugs, used in combination with neurotrophic

alleviating symptoms. The major challenge is

We have established novel rodent models

to develop safe, curative therapies, based on

where ischemic injury is restricted to the

enhancing the brain’s endogenous self-repair

cortex, enabling studies of functional recovery,

mechanisms. Neurotrophic factors such as

brain adaptations, neuronal rearrangements

Cerebral Dopamine Neurotrophic Factor

and transdifferentiation of non-neuronal cells.

(CDNF), Mesencephalic Astrocyte-derived

For Parkinson’s disease, we utilize toxin-based

Neurotrophic Factor (MANF) and Glial cell

(6-OHDA, MPTP, lactacystin), α-synuclein

factors, in protecting neurons in vivo.


We aim to use our models and tools: • to identify new neuroprotective drugs and microRNAs, plus their target genes and pathways, and evaluate their activity in promoting neuronal survival. • to alleviate endoplasmic reticulum stress as a way of treating protein-folding diseases in the brain. • to mobilize transcription factors, neurotrophic factors and microRNAs to stimulate endogenous self-repair mechanisms based on neuroprogenitor cells and reactive astrocytes. We are looking for pharmaceutical, academic, governmental and non-profit organizations as partners to support our mission in developing efficient treatments for devastating neurodegenerative diseases.

Drug therapies for neurodegeneration are still based on alleviating symptoms and the major challenge we have is to develop disease modifying therapies. 21


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Photomicrograph by M.Sc. Kert Mätlik


Jaan-Olle Andressoo

A novel approach to treating Parkinson’s disease Little is known of the therapeutic and scientific potential of elevating normal gene function at native sites of action, which is hypothetically enormous. Our main objective is to develop novel tools that will enable upregulation of the expression of specific genes in their native context, aiming to employ these concepts in therapy.

Our main approach is to target regulatory

delivery, with unknown consequences with

areas of genes, called 3´ UTRs. For proof

respect to side effects, treatment efficacy

of concept, we have studied the 3´ UTRs of

and behavior, that has been observed

two neurotrophic factors, GDNF and BDNF,

in previous studies in both experimental

that are already known to protect against

animals and humans. Our results, recently

Parkinson’s disease (PD). The development

published in PLoS Genetics (Kumar et al,

and maintenance of the brain involves

2015), imply that measures that promote

precisely controlled chemoattraction, elicited

elevation of endogenous GDNF levels may

by molecules such as neurotrophic factors

have clinical potential in the treatment of PD.

(NTFs), that are secreted by the brain’s own

Our next-generation results, based on this

cells. Because NTFs strongly promote the

concept, take us one step closer to defining

survival and function of adult neurons, they

a novel, viable treatment strategy for PD [for

have been proposed for the treatment of

reasons of confidentiality, we are able to

neurodegenerative conditions, such as PD.

disclose further details only under separate

Intracranial delivery of GDNF has already

agreement].

been and currently is in clinical trials for the treatment of Parkinson’s disease. However,

We are now looking for investment funding

this approach has adverse side-effects and

and/or commercial collaborations for testing

variable efficacy, hindering its clinical use.

endogenous GDNF/BDNF elevation as a therapeutic strategy, and for extending the

In our new approach, GDNF is not applied

proof of concept so as to generate better

ectopically, avoiding the massive sprouting of

disease models for validation of novel

dopaminergic fibers towards the site of GDNF

treatments.

Our main approach is to target regulatory areas of genes, called 3’UTRs. Jaan-Olle Andressoo, PhD Principle Investigator Institute of Biotechnology P.O. Box 56, Viikinkaari 5D FI-00014 University of Helsinki, Finland Tel. +358-2941 59394 GSM +358 503581213 jaan-olle.andressoo@helsinki.fi biocenter.helsinki.fi/bi/andressoo

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Susana Garcia

Targeting RNA toxicity in degenerative disorders

RNA toxicity results from mutations in genes

identify compounds that rescue locomotor

elegans model system has detected common

where a small region of just a few repeated

function, and thus hold therapeutic potential

modifiers of DM and one well-studied such

nucleotide-pairs is inappropriately amplified

in DM and similar diseases caused by

disorder, Huntington’s disease. This widens

in a repetitive manner. This leads not only

RNA repeat toxicity. Hits should include

the potential of our system in uncovering

to loss of gene function but also, when

modulators of alternative splicing, RNA

modifiers of toxicity, common to a broader

expressed, to toxic transcripts containing

clearance, and other cellular processes.

range of neurodegenerative disorders.

RNA toxicity is increasingly recognized as

Pre-clinical, early stage drug discovery with

The worldwide market for DM-related

a cause of human degenerative disorders,

a whole-animal model offers the advantages

therapies is estimated at approximately

from Amyotrophic Lateral Sclerosis (ALS) to

of “fast-fail�, since compounds that are

$2 billion, but there are currently no

Myotonic Dystrophies (DM), with a wide range

inherently toxic at the whole-animal level

approved drugs. Thus, our approach

of symptoms that include muscle wasting,

will be immediately rejected. Compared with

has high commercialization potential. A

weakness, cataracts, heart conduction

traditional drug-screening platforms, our

provisional patent has been filed on our C.

defects and insulin resistance. These

approach is faster, more economic, and can

elegans model and we are in the process of

disorders are predicted to share mechanisms

be automated with high-throughput scaling,

establishing it as a platform to screen small

that lead to cellular dysfunction and disease.

key components for the rapid identification of

molecule libraries including FDA approved

Currently they are managed only by early

new therapeutics. We have recently identified

compounds. In the second phase, we will

detection and palliative treatment, costing

a previously unknown genetic suppressor of

license leads to established pharmaceutical

several billion dollars annually but with little

RNA toxicity, the nonsense-mediated mRNA

companies that have expressed interest

return in terms of improved quality of life.

decay (NMD) pathway, which is conserved in

in developing DM-targeted therapeutics,

humans, allowing for rapid translation into

reinvesting licensing revenue into additional

Our research focuses on DM, affecting

human cell-lines for further validation, with a

screens and disease-model development.

at least 1 in 8000 people worldwide, and

high expectation of success.

We are looking for partners interested

the expanded repeats. Expanded repeat

constituting a paradigm for RNA toxicity in

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in investing in the identification of these

disease pathogenesis. We have developed

RNA toxicity has recently been implicated

an animal model of DM, using the worm C.

as an additional pathological mechanism in

elegans, providing an opportunity for high-

a subset of disorders previously believed to

throughput small-molecule screening to

result only from protein repeats, and our C.

candidate molecules for commercialization.


Our research focuses on Myotonic Dystrophies, an RNA-based disorder affecting at least 1 in 8000 people worldwide.

Myotonic Dystrophy (DM) worms exhibiting one of the proteins disrupted in DM, tagged with red fluorescence - the splicing factor MBNL-1. The toxic repeat-bearing RNAs expressed in DM worms can be detected as green fluorescence.

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Tommi Kajander

Synaptic adhesion molecules - making neuronal connections to combat cognitive disorders

Neurons form a vast network of connections

Synaptic adhesion molecules are able to

connectivity in cell culture. Starting from cells

that underlie all brain functions. Synapses,

induce synapse formation by binding to their

derived from patients, where dysfunction

where one neuron connects with another,

receptors on the target cells, where synaptic

of synaptic adhesion receptors is the

depend on specific adhesion proteins.

differentiation then begins. This involves the

underlying cause of disease, we will use the

They are required for synaptic assembly,

accumulation of different adhesion proteins

technology of induced pluripotent stem-cells

maturation and stability, and thus play a

and expression of ion channels on the

(iPSC) to build disease models that could

central role in the formation and function of

post-synaptic side, mediated by intracellular

be used in future as a platform for drug

the brain. Moreover, dysfunction of synaptic

organizer proteins such as PSD-95 or GRIP.

screening or for testing other personalized

adhesion molecules is linked to specific

We currently focus on studying the molecular

therapeutic strategies. Finally, we plan to

cognitive impairments such as schizophrenia,

structures and interactions of the synaptic

conduct small-molecule screens to identify

autism and bipolar disorder.

leucine rich repeat (LRR) adhesion molecules

compounds able to enhance or inhibit

and their pre-synaptic ligand-adhesion

synapse formation, specifically targeting the

Our broad scientific goal is to dissect the

receptors, protein tyrosine phosphatase

activity of the LRR adhesion proteins. For all

molecular details of how these proteins

receptors and neurexins.

of these endeavours, we are eager to identify

interact, how they are regulated and

industrial and academic partners, as well as

expressed, and what are the results of

We are working to establish several

their inhibition in vitro. This way we hope to

applications for recombinant synaptic

understand the formation and dynamics

adhesion molecules in basic research,

of synaptic structures and decipher how

together with a wide network of

synaptic adhesion proteins are involved in

collaborators. For instance, we are using

disease. A longer-term goal is to translate

these proteins to screen for new ligands

this knowledge in to clinical use, by creating

and functions, by affinity purification and

tools to treat and eventually cure and prevent

proteomics. Using adhesion protein-

cognitive disorders, which represent a huge

patterned surfaces, we will study their

societal burden.

effects on synapse formation and neuronal

funders.

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Small Molecule Pharma

Understanding mitochondrial protein synthesis for better targeting of therapeutics | Brendan Battersby Novel targets to combat RNA viruses | Sarah Butcher Leukocyte beta2-integrins in health and disease | Susanna Fagerholm BMH-21, a unique anticancer molecule targeting Pol I | Marikki Laiho Twinfilin and cyclase-associated protein inhibitors for preventing cancer invasion and chemoresistance | Pekka Lappalainen Discovery of substrate-selective small molecule proteostasis modulators | Ville Paavilainen

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Brendan Battersby

Understanding mitochondrial protein synthesis for better targeting of therapeutics

The goal of my research programme is

mitochondrial targets of antimicrobials is

in cancer cells, where they may become

to understand how biological circuits are

therefore crucial to enhancing the specificity

essential for cell survival.

established in the cell for the synthesis of

of these molecules and reducing their toxicity

the distinct subset of 13 proteins required

to humans.

for aerobic energy metabolism. These

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Fundamental research in my laboratory is thus generating a molecular understanding

proteins are synthesised in a unique cellular

We have established that the 13

of how acute and chronic disruption to the

compartment, the mitochondria, which acts a

mitochondrial DNA-encoded proteins are

quality control of mitochondrial protein

metabolic hub and energy generator for the

synthesised in excess of demand so that at

synthesis is linked to cellular function. This

cell. We focus on discovering the molecular

least 80% of newly synthesised mitochondrial

paradigm will provide insight into how

mechanisms at key regulatory nodes in the

proteins are degraded, thus minimizing the

mitochondrial homeostasis is disturbed

pathways of mitochondrial protein synthesis,

errors that arise naturally during protein

by different types of pharmacological and

and the response to acute and chronic

synthesis and folding. The cell requires a

genetic insults. On the one hand, this will

disruptions, both of pharmacological and of

tightly regulated quality-control pathway

enable better targeted therapies to limit

genetic origin.

to ensure that this labile pool of potentially

such damage, which can be applied, for

harmful proteins is degraded and does not

example, in neurodegenerative disorders.

Protein synthesis in mitochondria is

over accumulate. My current research has

On the other, it can also be exploited as a

molecularly similar to that in bacteria. Since

shown how genetic and pharmacological

novel cytotoxic strategy, leading to more

various classes of antibiotics target protein

disruptions to this protein turnover pathway

precise treatments for cancer. Finally, it will

synthesis, a potentially toxic side-effect of

can be deleterious to the cell and is the

inform the development of next-generation

antibiotic usage is disruption of mitochondrial

underlying molecular defect in a number of

antibiotics, free from damaging side-effects.

protein synthesis, which can have profound

inherited human diseases. Typically, these

effects on human health. Identifying the

quality control pathways are also upregulated


Mouse (skin cell) fibroblast stained for mitochondria (red) and alpha-tubulin (green). Mitochondria move throughout the cell on the microtubule cytoskeleton that is composed of alpha and beta tubulin. Image by Paula Marttinen

31


Sarah Butcher

Novel targets to combat RNA viruses Though non-enveloped icosahedrally-symmetric ssRNA viruses are one of the largest groups of viral pathogens, their assembly mechanisms are still poorly understood. The control of ssRNA viruses by vaccination is unlikely to ever be possible for all but a small subset of viruses, so innovative routes to antiviral therapy are urgently required. Our group has identified sequence- and structure-specific nucleotide motifs within the genome of a human picornavirus that play a key role in virus assembly. Referred to as “packaging signals�, due to their cooperative interaction with the key structural viral proteins (capsid proteins), these motifs overlap untranslated and coding regions. Viral assembly is therefore in competition with other functions of the genome. Disrupting these high affinity packaging signal-protein contacts has deleterious consequences for capsid assembly, and thus presents a novel antiviral drug target. For a given single-stranded RNA (ssRNA) virus species, the packaging signals share certain common features that increase the number of target sites per virus per drug, and show a lowered genetic variation between strains. Drugs targeting such sites will be highly disruptive to ssRNA virus assembly and will not be easily defeated by the development of resistance. Thus, our strategy offers potential new therapies against clinically relevant viruses such as poliovirus, hepatitis C (significant chronic infection), and rhinovirus (causing the common cold: economic costs annually in the tens of billions of dollars).

We have established a wide range of

or bind to packaging signals of RNA viruses

systematic analysis of all molecular reactions

experimental and theoretical tools for

that function in viral capsid formation. It

(interactome), with structure-function studies

the identification and characterization

describes pharmaceutical and plant viral

on emerging viruses.

of packaging signal function(s) in capsid

control compositions for use in the treatment

assembly, revealing a previously unsuspected

of viral infections; methods to treat viral

With an appropriate pharma partner, our

principle in the assembly of single stranded

infections; and five methods to screen for

existing targets plus our capability to produce

RNA viruses. The implications have the

packaging signals in viral RNA genomes.

additional targets could be harnessed

potential to transform our understanding of

32

to deliver a powerful new range of anti-

the fundamental biology of these systems,

A second approach we employ aims to identify

viral treatments. We thus require further

including the mechanisms of infection and

the key interactions between pathogenic RNA

investment for drug screening, mammalian

evolution.

viruses and the human host, so as to describe

animal models and 3D cell culture, to progress

the molecular pathogenesis of the infections,

this technology to phase-one drug trials.

The patent we have applied for relates to

and identify novel targets for antiviral agents

targets for anti-viral agents that either mimic

and diagnostics. This approach combines a


Image courtesy of Pasi Laurinmäki

33


34


Susanna Fagerholm

Leukocyte beta2-integrins in health and disease

The immune system is of fundamental importance for human survival as it functions to protect us from disease. However, it also poses a significant threat to the individual, as immune cell-mediated diseases such as autoimmunity and allergy are becoming increasingly common. We are interested in leukocyte beta2-integrins, important cell surface receptors in leukocytes which

Specific projects:

regulate both adhesion and signaling in immune cells.

Integrins and SLE. Certain integrin genetic variants are strongly associated with systemic lupus erythematosus (SLE), an autoimmune disease with

Integrin-mediated cell adhesion, migration and signaling

a significant genetic component. By studying these variants and their

is crucial for proper immune system function. Studying

signaling capabilities in vitro and in vivo, we aim to reveal novel therapeutic

these processes is therefore fundamental for our

targets for autoimmune disease. The cell- and animal models we have

understanding of immunity. Importantly, integrins are

already produced, or aim to establish, will also be used in future drug-

also recognized therapeutic targets. Our group studies

development programs aimed at creating more specific therapies for

the in vivo roles and regulation of leukocyte beta2-

autoimmune disease, in a personalized medicine approach.

integrins both in the healthy and the dysfunctional immune system, using novel animal models. In addition,

Integrins and cancer. We have recently revealed that integrins work as

we aim to elucidate the role of these receptors

a “brake� in certain immune cells, restricting their signaling, activation

in immune-related diseases such as allergy and

and migration. By targeting integrins and/or their signaling pathways, we

autoimmunity, and investigate their possible targeting

therefore aim to modify immune cell behavior to optimize treatment of

to modify immune responses in diseases such as cancer.

disorders with an immune-related component, such as cancer.

35


Marikki Laiho

BMH-21, a unique anticancer molecule targeting Pol I Current studies on cancer pathway alterations are focused mostly on cancer genome abnormalities, their impact on the cancer phenotype, and how they can be targeted therapeutically. However, cancer cells also become dependent on specific cellular metabolic pathways, which include the need for an increased rate of protein production. This ultimately depends on the synthesis of rRNAs, governed by RNA polymerase I (Pol I), and on the program of ribosome biogenesis. The Pol I transcriptional machinery is highly responsive to oncogenic stimuli and commonly deregulated in cancer. Yet, this program has not been viewed as a clinically relevant target and very few attempts have been made to manipulate it.

Pol I has traditionally been considered to

I complex. It has broad anticancer activity as

Pol I complex assembly and stability, aiming

have a housekeeping function that cannot be

tested in the NCI60 cancer cell panel, with a

to identify factors that mediate deregulated

interfered with, and thus to be undruggable.

potent GI50 of 0.16 ÂľM. BMH-21 is cell and

Pol I transcription in different cancers. Via

No markers have been developed to assess

tissue permeable, orally bioavailable, and

chemogenomic profiling of BMH-21 activity,

Pol I transcription rates that would support

has low toxicity in normal cells compared to

we are attempting to identify factors that

clinical decision-making, and therapeutic

cancer cells. We have conducted structure-

sensitize cancer cells to Pol I inhibition. At the

development towards Pol I is thus still in

activity relationship analyses of BMH-21

same time, we are proceeding with target-

its infancy. In response to the critical need

by developing over 40 analogs, and so far

based chemical biology screens to identify

to develop Pol I-targeting drugs, and to

identified several equipotent derivatives. The

new Pol I inhibitors.

conduct proof-of-principle studies, we have

physicochemical characteristics of the active

introduced a novel small-molecule compound

analogs define the activity of the molecule

Our long-term goals are to develop Pol I

(BMH-21), that targets Pol I activity. This

in a tightly defined chemical space. BMH-21

targeting, using BMH-21-like molecules,

represents a new therapeutic candidate in

demonstrates promising activity in preclinical

as cancer therapies. Studying its activity in

cancer, with huge potential impact.

mouse models, with significant inhibition of

combination with other cancer intervention

tumor growth in melanoma, prostate and

strategies should reveal further opportunities.

colon carcinoma models.

We have patents issued and pending on

BMH-21, a unique pyridoquinazolinecarboxamide, was

36

BMH-21 and its derivatives in the US and

discovered in our high-throughput screen

Given that Pol I deregulation occurs at very

Europe. The work is a collaboration between

for anticancer small-molecules. We have

high frequency in cancers, we predict that a

my labs in Helsinki and Johns Hopkins

demonstrated that it acts by blocking

Pol I targeting approach could have a major

Universities, with intellectual property jointly

Pol I transcription and brings about the

impact in many cancer types. To support this,

owned, but managed by the Johns Hopkins

destruction of the catalytic subunit of the Pol

we are conducting mechanistic studies on

University Technology Transfer Office.


37


Pekka Lappalainen

Twinfilin and cyclase-associated protein inhibitors for preventing cancer invasion and chemoresistance We use a combination of genetics, cell biology, and biochemistry to study the role of the cytoskeleton in cancer. Our main aim is to elucidate the structural and biochemical basis of the cancer-associated functions of two key cytoskeletal proteins, twinfilin-1 and cyclase-associated protein (CAP), which promote cancer cell invasion and chemoresistance.

Coordinated building and break down of the

Our studies have revealed the molecular

actin cytoskeleton gives the cell the ability

mechanisms whereby twinfilins control actin

to undertake many fundamental cellular

filament assembly. The mammalian non-

processes such as migration, morphogenesis,

muscle twinfilin isoform, twinfilin-1, has been

adhesion, and cytokinesis. Defects in its

linked to progression and chemoresistance

organization and dynamics are therefore

of breast cancer and lymphomas. Its

central in cancer. Progression to malignancy

suppression delays lymphoma progression

involves the dysregulation of multiple actin-

in mice, and extends animal survival

driven processes. Consequently, several

following chemotherapy. Furthermore, it was

actin-binding proteins have been directly

identified as the major functional target of

linked to cancer invasion and metastasis,

the regulatory micro-RNA miRNA30c, which is

notably twinfilin-1 and CAP.

already used as a prognostic marker in breast cancer. Twinfilin-1 depletion dramatically

Twinfilins are highly conserved proteins that

inhibits invasion and spread of breast-cancer

regulate cytoskeletal dynamics in a variety

cells and makes them more sensitive to

of cell-types. CAP is a large multifunctional

chemotherapy agents.

protein which promotes actin recycling. Elevated expression levels of CAP and

These studies allow us to design screens to

twinfilin-1 are associated with many

identify specific twinfilin-1 and CAP inhibitors

cancers, whilst CAP depletion inhibits the

from small compound libraries. These will

proliferation and invasion of breast-cancer

serve as useful proof-of-principle compounds

cells. These molecules have therefore

for developing new drugs for use in cancer

emerged as promising new targets for cancer

chemotherapy.

chemotherapy.

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39


Ville Paavilainen

Discovery of substrate-selective small molecule proteostasis modulators We are investigating the fundamental question of how protein molecules are correctly targeted to their final cellular locations or to the extracellular environment. This targeting is achieved by a host of cellular factors that recognize distinct sequence features in newly-made proteins and deliver them to their ultimate functional destinations. We focus on dissecting and functionally classifying the chemical information contained in these protein-targeting ‘zip codes’ as well as identifying the cellular machineries responsible for protein transport to correct locations. Many diseases are associated with dysregulated protein transport and secretion. Therefore, we are exploring the protein targeting zip code as a novel druggable motif amenable to small-molecule modulation. About 30% of all proteins are secreted

are exploring the possibility of preventing the

for differentiating between functional and

outside of the cells or integrated into

production of specific, mislocalized proteins

non-functional secretory zip codes and are

cell membranes. Secreted and integral

associated with disease, by discovering potent

using this system to collect vast amounts of

membrane proteins enable cells to exchange

small-molecules with the ability to prevent

functional sequence data, which will allow

information and respond to their specific

their biosynthesis. In this work, we explore

development of different sequence prediction

environments. They act as signaling receptors

naturally occurring small molecules that have

algorithms. In addition to allowing accurate

and enable transport of molecules across

evolved to target the particular branches

prediction of secretory protein function from

membranes. Most importantly, they represent

of the protein homeostasis machinery with

genomic data, this method will also act as

the majority of current drug targets.

highly specific mechanisms of action.

a powerful tool for identifying and profiling

Our work in this area has two goals. First,

We have thus far demonstrated the ability

inhibitors with ability to prevent the creation

we aim to understand the biological roles

of diverse natural product small molecules

of different disease-associated proteins.

of the protein secretion apparatus and

to selectively prevent the formation of only

how its function is altered in disease

a subset of secreted proteins, and have

We envision that new substrate-selective

states. We aim to functionally identify and

evidence that these compounds target

proteostasis modulators can serve not only

classify information contained in secretory

specific recognition elements of the secretion

as powerful molecular probes, but also as

zip codes and build accurate tools for

machinery. We are currently working on

lead molecules for the development of future

predicting secretory protein function from

identifying new drug-like natural products and

therapeutics. These compounds would

genomic sequence data. Such tools will

natural product-inspired small molecules that

have much higher selectivity than current

allow prediction of secretory protein loss-

can prevent biogenesis of different subsets

inhibitors of components of the proteostasis

of-function by scanning disease genome

of secreted or membrane proteins. We have

machinery, such as the proteasome or

sequences for point mutations. Secondly, we

established a novel technology platform

cellular chaperones.

mechanistically unique secretory protein

40


Secreted and membrane proteins constitute approximately 30% of the human proteome and many are important drug targets. Yet, their targeting with small-molecule therapeutics has remained a daunting task.

41


Cell & Protein Technologies

Craniofacial regeneration: from Evo-Devo to therapeutic applications | Nicolas Di-Poi “GO IIST” | Hideo Iwai Stem cells and aging | Pekka Katajisto DNA Dream Lab – effortless realization of dream constructs | Konstantin Kogan Decline of the denture: Using stem cells to regrow our teeth | Frederic Michon Novel peptides and drugs to direct differentiation of stem cells | Osamu Shimmi Actin-regulated transcription in cancer and laminopathies | Maria Vartiainen Profiling cellular quiescence to develop novel anti-cancer drugs | Norman Zielke

43


Nicolas Di-Poi

Craniofacial regeneration: from Evo-Devo to therapeutic applications Developmental & Stem Cell Biology has become a crucial field for the understanding of tissue regeneration and the implementation of regenerative medicine. The ability to repair or regenerate tissue is a fundamental property present in all multicellular organisms, but there is tremendous diversity in how this process occurs within vertebrates. In particular, adult mammals (including conventional experimental models such as mice and rats) have limited regenerative capacities compared to other model organisms such as reptiles. These offer one of the best examples of regeneration in vertebrates. Hence, studying such taxa is a priority for improving our general understanding of tissue development, patterning and regeneration. Importantly, it should help identify new targets and/or new therapeutic approaches for regenerative medicine.

Our laboratory is investigating the molecular

studies, because of their excellent fossil

regeneration, they identify new targets and

genetic basis of the development, evolution

record, and because they show high levels

approaches for the treatment of common

and regeneration of different craniofacial

of morphological variation and adaptive

human disorders such as neurodegenerative,

tissues (tooth, retina, brain) with unique

innovation. This is of crucial importance in

retinal, and dental degenerative diseases.

regenerative capacity in non-classical reptilian

understanding tissue development from an

Our systematic approach, combining

models (lizards and snakes). Surprisingly,

evolutionary perspective, which will be needed

Evolutionary Developmental Biology (Evo-

in contrast to the long-lasting interest in

to promote regenerative capacity in humans.

Devo) with Regenerative/Stem Cell Biology is

craniofacial development in mammals, and

44

unique not only in Finland, but worldwide.

the numerous studies resulting from it,

Our research projects use a multi-disciplinary

relatively little is known about the embryonic

approach that deploys state-of-the-art,

Our recent data already indicate that reptile

development and adult regeneration of these

methods combining molecular embryology,

studies carry enormous potential and high

tissues in other vertebrate classes. Our focus

genetics, 3D imaging, phylogenomics,

relevance to common human diseases, since

on craniofacial research is motivated by the

morphometrics, and theoretical modeling.

reptilian tissue structural and functional

fact that craniofacial diseases and disorders

The extensive analysis of reptilian models

circuitry, neuronal and epithelial cell types, as

account for a considerable and increasing

helps us to understand why and how

well as signaling pathways are exceptionally

portion of health problems worldwide. In

regeneration in mammals is absent or

well conserved (see, e.g., Di-Poi et al., Science

addition, craniofacial organs are perfect

limited. In addition, by revealing the

Advances 2016; Milinkovitch, Di-Poi et al.,

targets for evolutionary and ecological

molecular and cellular principles underlying

Science 2013; Di-Poi et al., Nature 2010).


Understanding the key signaling pathways of craniofacial tissue regeneration in reptiles will allow us to design preclinical tests of therapeutic strategies in mammalian models and human cell/ organ culture leading to ground-breaking clinical applications.

45


46


Hideo Iwai

“GO IIST” The IIST system, standing for Ion Inducible Self-cleavage tag, is a new technology for protein purification and ligation, with wide applications. Every year, the number of peptide-, protein- and antibody-based drugs entering clinical trials is steadily increasing. There is a pressing demand for more cost-efficient and effective approaches to the production of peptide-based conjugates for this market. The IIST system, based on patented technology developed by Dr Hideo Iwai in BI, University of Helsinki, is a novel and cost-effective way of achieving this goal. Based on natural or engineered protein-segments with self-cleavage activity, IIST can support many uses both in basic research and in industry. In a conventional approach to protein purification and conjugation, a tagged protein of interest has to be treated with expensive proteases following the affinity-capture step. These proteases also need to be removed in a final recovery process. IIST eliminates the need for expensive proteases, by making use of the ion-inducible self-cleavage activity of the IIST domain, located between the protein of interest and the tag. The final recovery step needs only a re-use of the affinity column, since the only thing that needs to be removed from the final product is the tagged IIST domain.

The global market for protein therapeutics, including monoclonal antibodies, is expected to reach $165 billion by 2019.

Applications include not only the purification of proteins and peptides, but also the conjugation of protein and peptide fragments, peptide cyclization and amidation, and antibody conjugation to drugs or immunotoxins. The conjugation step is enabled by IIST because of its inherent protein-splicing activity. The global market for protein therapeutics, including monoclonal antibodies, is expected to reach $165 billion by 2019. To bring this new technology to market needs the involvement of one or more commercialization experts or an ‘entrepreneur-in-residence’ to strengthen the research team, plus the interest of industrial collaborators and potential investors.

47


48


Pekka Katajísto

Stem cells and aging Young stem cells renew tissues constantly,

We have thus established a new scientific

but old stem cells can no-longer support

paradigm of age-selective organelle

functional tissue renewal at the required

segregation. At the same time we have

rate. The resulting decline manifests as aging.

developed a unique set of research tools to

Stem cells fail at their regenerative task

label subcellular components in an age-

due to the damage they have accumulated.

specific manner, and then follow their fate

We investigate the mechanisms that have

inside live and dividing stem cells. Together,

evolved to minimize damage accumulation in

this concept and toolkit enable us to address

stem cells, and how such mechanisms could

important research questions that are

provide points for intervention in aging-related

inaccessible to anyone else. Our current work

diseases and even the aging process itself.

aims to determine how stem cells recognize the age of their organelles, and how age-

One possible way for nature to reduce

selective segregation is regulated.

damage in a stem-cell lineage would be to selectively apportion damaged components

Once we have identified the molecular

away from the new stem cell during

mechanisms underlying this phenomenon,

asymmetric cell division. We have discovered

we will address how to induce or modify

that stem cells do, indeed, harbour distinct

age-selective organelle partition, with the

populations of intracellular organelles

following aims in view:

of different ages, and that certain old

• clear away damaged components from

organelles, for example the mitochondria, are asymmetrically segregated at stemcell division, and become enriched in the differentiating daughter cell. In other words, this novel mechanism potentially ensures that stem cells retain young and ‘fit’

stem cells after harmful events • rejuvenate old stem cells, so as to promote renewal of old tissues • reduce the risk of aging-related diseases and, by combining these goals • slow down the aging process itself

organelles, whilst purging themselves of old and possibly damaged, cellular components,

Our group is keen to attract funders,

which are selectively partitioned into the

investors and industrial partners to help us

differentiating cell lineage.

turn our discoveries into viable technologies to limit, delay and eventually reverse aging.

49


DNA Dream Lab

50


Konstantin Kogan

DNA Dream Lab – effortless realization of dream constructs DNA Dream Lab (DDL) is a new initiative at BI that aims to serve life-science users, initially in the Helsinki area, but with the potential to serve the whole of Finland and beyond. DDL is a one-stop-shop facility for plasmid DNA. It is widely acknowledged that most genetic manipulations revolve around plasmid DNA, since fast and accurate molecular cloning is at the core of almost any life-science project nowadays. Our mission is to help both basic and industrial researchers in two major directions: consultation and implementation. Plasmid DNA consultation services include

experiments. This greatly impacts how the

providers at cost. We accept students to

realization of customer needs by searching

experimental set-up is planned by a lab

implement their own cloning under our

for and designing optimal solutions, with

researcher using our services.

supervision using our materials, protocols,

emphasis on the experiment where these

and instrumentation. Upon agreement with

plasmids are going to be used. Simplicity,

Plasmid DNA implementation services

researchers, we disseminate the plasmids

price, and time are the criteria for selecting

complements the plasmid DNA consultation

as well as all the available information; yet

the most suitable strategy. Plasmid DNA

part. Here we use state of the art methods

keep private unpublished plasmids, or

experts perform the search using a number

in DNA cloning, most of which are sequence

those having patents pending approval.

of external service providers (e.g. gene

and ligation independent (e.g. SLIC, RF,

We implement custom-made information

synthesis companies, plasmid depositories,

Gibson Assembly, LCR, USER). To make the

technology solutions to allow immediate

local and international cDNA collections)

service complete we also securely store

access, search, and retrieval of any publicly

as well as DDL’s own comprehensive and

DNA collections of our customers, having

shared item fast, easily, and cheaply, due to

constantly growing local depository. Our

backups in three different locations, stored

concise and proper annotation of every single

deep knowledge and expertise in structural

in three different forms. Depending on the

plasmid, and automated storage systems.

and molecular biology and protein folding,

design, we outsource some of our activities

We deliver ready-to-use plasmid DNA for any

coupled with years of experience in

to leading companies in gene synthesis, oligo

experiment in any required amount or purity

plasmid construction, form a solid basis for

manufacturing, and sequencing.

to any place in the world.

awareness of downstream applications and

Being a not-for-profit, academic organization

We are looking for appropriate funding and

our ability to obtain any required number

we are completely transparent in our

partnerships to expand and develop our

of plasmids of almost any complexity allows

activities whether it is in design, production

services.

for the specific design of constructs to

or management, making use of open-source

increase the success of our client’s further

technologies or outsourcing to licensed

high-quality design of plasmid DNA. Our

51


Frederic Michon

Decline of the denture: Using stem cells to regrow our teeth Historically, an important goal of developmental biology has been to obtain the knowledge needed to achieve the regeneration of tissues and organs. Understanding developmental mechanisms, and the underlying networks of regulatory genes, is instrumental for future tissue and organ bioengineering. We also need to understand the properties of the stem and progenitor cells and the cues that induce their differentiation. Recent progress in stem-cell research has led to realistic bioengineering of tissues such as bone and cartilage. However, to regenerate whole organs composed of several cell lineages is far more challenging and needs a deeper understanding of organogenesis and the roles of different classes of stem cells.

Several organs in vertebrates develop as

continuously growing front teeth of mice.

on the specification of the dental epithelial

appendages of the outmost layer of the

Their renewal is fueled by two specialized

tissues, responsible for the hard enamel

embryo, called the ectoderm. These include

stem-cell niches located at the base of the

(tooth crown), and tooth attachment to the

hair, feathers, scales, nails, teeth, cornea,

tooth, providing an excellent model to study

jaw. Our current work is showing the crucial

lachrymal and mammary glands. Their

dental stem-cell biology.

role of the dental Sox2-expressing cells in the neo-formation of teeth, ex and in vivo.

development shares similar molecular and

52

morphological mechanisms, leading to the

We aim to elucidate the genetic basis of dental

formation of functional organs. While some

tissue identity, and the origin and lineages of

The anticipated results will help us

ectodermal organs are heavily studied, less

dental stem cells. As part of a pan-European

understand how dental stem-cells determine

is known about dental stem cells. The human

research collaboration, our goal is to establish

tissue identity, and may be applicable to

tooth is not a renewing or cycling organ.

a clinically applicable tooth bioengineering

other ectodermal organs. Even though dental

However, stem cells have been identified in

protocol. To achieve this, we need to find

aberrations can nowadays be treated, the

the dental pulp and periodontal ligament,

out what determines the fate of dental stem

loss of teeth still has a dramatic impact on

which can give rise to hard dental tissues.

cells, and the genetic networks involved in

human health and self-esteem, and requires

These stem cells are not able to generate

their maintenance and differentiation into

a wide spectrum of expensive medical

whole new teeth: this will undoubtedly

specific cell lineages. This will enable us to

interventions over the lifetime of a patient.

require us to understand their biology in

design in vitro differentiation protocols that

Our research will lead to improved clinical

greater detail. Our current research, started

are the crucial first step towards the dream

treatment and prevention of dental defects,

in Prof. Irma Thesleff’s lab, focuses on the

of dental bioengineering. Our main focus is

in particular loss of teeth.


Photo courtesy of Jukka Jernvall

53


Osamu Shimmi

Novel peptides and drugs to direct differentiation of stem cells Members of the Bone Morphogenetic Protein (BMP) family have been associated with many pathologies, including vascular diseases, obesity, diabetes and cancer. Several BMPs have been shown to be clinically useful, and BMP2 and BMP7 have been approved for treatment of spinal fusion, fracture healing and dental tissue engineering. The BMP2:BMP6 heterodimer has also been proposed for use in vitro to promote the differentiation of embryonic stem cells (ESCs).

Implantation of BMPs together with

Drosophila BMPs to understand the ways

improved. Combined with our knowledge

autologous stem cells has emerged as a

in which they have become functionally

of how evolution has shaped Scw, we aim

promising technique in tissue engineering,

optimized during evolution. The Drosophila

to develop a superBMP, as an efficient

aiming at the regeneration of various body

BMP5-8-like protein Scw is in a unique

and specific differentiation factor for stem

parts. However, large-scale production of

position since it is exclusively expressed in

cells. Such a product should be applicable

BMP ligands remains costly due to multiple

the early embryo and is evolutionarily highly

for differentiation of stem cells into

preparation and purification processes,

derived. Scw is required for generating peak

chondrocytes, osteoblasts or cardiomyocytes.

and clinically effective doses of such

levels of the BMP gradient in Drosophila

This will involve not only optimization of the

recombinant BMPs are much higher than

embryos. Thus, its protein sequence appears

peptide sequence, but also post-translational

their physiological levels. To overcome these

to have evolved to provide maximal biological

modifications that can have a profound

issues, development of a novel, “superBMP�

activity. We have also shown that post-

effect on its potency, specificity, stability and

agonist is desired. One such way is to develop

translational modifications of Scw modulate

solubility.

ligands with improved bioactive properties

BMP signaling activity both in vitro and in vivo.

through increased solubility, stability and receptor affinity.

54

We are looking for partner organizantions We postulate that tolerance for structural

to help us implement the various technical

changes of BMPs is dependent on a range of

steps in our project, enabling us to produce

Due to the fact that BMPs play crucial

developmental and evolutionary constraints.

and evaluate BMP variants based on our

roles in many different contexts in animal

By employing optimized sequences through

predictions. These approaches will create and

development, their protein sequences in

natural selection of novel peptides, the

develop novel products for commercialization

mammals are highly conserved. We study

biological properties of BMP ligands can be

in the regenerative medicine sector.


55


Maria Vartiainen

Actin-regulated transcription in cancer and laminopathies Actin operates in the cell’s cytoplasm as a key part of the cytoskeleton, which provides the cell its shape and enables movement. The actin cytoskeleton is therefore critical for cell migration, which is a pre-requisite for cancer metastasis. Thus, it is not surprising that it is deregulated not only in many cancers, but also other diseases, which show disturbed tissue architecture. In recent years, we discovered that actin plays an important second role in cellular processes, inside the cell nucleus as well, where it influences gene expression. This provides a mechanism whereby actin could contribute to disease development and progression independently of its direct effects on cell structure and motility. Our data also supports the involvement of nuclear actin in laminopathies. These are a group of genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina, the fibrillar structure responsible for the internal organization of the nucleus. Laminopathies display a large variety of clinical symptoms, such as skeletal and cardiac muscular dystrophy, lipodystrophy, diabetes, and premature aging, progeria. One conceptual puzzle with laminopathies has always been the fact that, whist they mainly affect specific tissues, the underlying genes are expressed everywhere in the body.

Nuclear actin and cancer

pathways. This will not only shed light on the

components of the nuclear lamina, and we

The hallmark of cancer cells is unregulated

basic mechanisms of cancer progression. It

are currently analyzing their relevance for

growth. However, most cancer deaths are

will identify novel targets and molecules for

MKL1-SRF-regulated gene expression. Here

not due to the primary tumor, but rather

diagnosis and, importantly, a new generation

too, high-throughput screening will help us

the spread of cancer cells, metastasis, to

of more effective anti-cancer drugs.

identify novel regulators and small molecule

other organs. In normal cells, cell growth

56

targeting the pathway, and test their ability

and migration are tightly regulated by many

Nuclear actin and laminopathies

to correct impaired MKL1–SRF signaling in

signaling pathways and transcriptional

In collaboration with researchers from the

laminopathic cells. These approaches should

programs. Nuclear actin has been shown

US, we demonstrated a novel mechanism

enable us to ameliorate the drastic cardiac

specifically to regulate two transcriptional

that could provide insights into the

pathology associated with laminopathies.

programs critical for cancer progression:

cause of the cardiac phenotype in many

the growth-regulating Hippo-pathway and

laminopathies. We showed that two

Perspective: We seek major funding to

metastasis-regulating MKL1-SRF pathway. Our

components of the nuclear lamina, lamin

support our high-throughput screening

preliminary data reveals extensive connections

A/C and emerin, modulate nuclear actin

pipeline, aiming to identify compounds to test

between these two programs, and we are

and thus regulate gene expression through

further in cell and animal models of cancer

examining how this crosstalk influences

the MKL1-SRF pathway. This regulation is

progression and laminopathy, ahead of

cancer progression. By high-throughput

disrupted in laminopathies. Subsequently we

clinical trials.

approaches, we aim to identify common

discovered a physical association between

players and small molecules targeting both

the transcription coactivator MKL1 and


57


Micrograph of an eye imaginal disc derived from the fruit fly Drosophila melanogaster, in which their characteristic cell cycle pattern was visualized with the Fly-FUCCI (fluorescent ubiquitination-based cell cycle indicator) system (Zielke et al. 2014). Cells residing in G1 phase were marked in green; cells in S phase were labeled red and cells in G2 phase were labeled yellow. Image courtesy of N. Zielke and H. Lorenz (ZMBH – Imaging Facility).

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Norman Zielke

Profiling cellular quiescence to develop novel anti-cancer drugs The tissues and organs of multi-cellular organisms are comprised of specialized cell types, which originate from stem cells. Stem-cell pools are typically heterogeneous in regard to many cellular processes, including transcription, cell signaling, proliferation status, and susceptibility to apoptosis. Superficially minor differences between cells can have a profound impact on cell fate. Heterogeneity is also found in most tumors, resulting in differential sensitivities to cytotoxic or anti-proliferative drugs. Our work aims to develop and exploit tools that can discriminate between superficially similar cells that differ in key properties such as proliferation status and drug susceptibility.

Understanding the characteristics of

quiescent cells, or aimed at releasing them

status of stem cells e.g. in the posterior

quiescent stem cells has been hampered

from quiescence to make them susceptible to

signaling center (PSC) of the Drosophila lymph

by the rarity of these cells in many tissues.

conventional treatments.

gland or the intestinal stem cells (ISCs) in

To bypass this limitation, we are currently

the regenerating midgut. We are currently

developing a biosensor that facilitates

FUCCI (fluorescent ubiquitination-based cell

developing a next-generation FUCCI sensor

detection and purification of quiescent cells.

cycle indicator) biosensors are a promising

that allows robust detection of quiescent cells

The isolated cells can be further analyzed by

approach for studying cell proliferation at

in flies and mammalian cell culture.

various omics methods, thereby providing

single-cell resolution. By assigning specific

novel insights into the transcriptome,

fluorescent labels to different cell cycle

We aim to develop this technology further

and the epigenetic status of quiescent

stages, it provides a reliable readout for cell

in two directions: first, we plan to use it to

cells. In addition, this reporter system can

proliferation that can be applied to live-cell

assess how variability of the proliferation

aid screening for novel, more effective

imaging or high-content screening. Combined

status affects cell-fate decisions. This will

anti-cancer drugs. Many conventional

with flow cytometry it enables detailed

help us to understand how abnormalities in

chemotherapeutics target key regulators of

molecular characterization of isolated single

cell-fate programming in stem cells can lead

cell proliferation. However, a large fraction

cells. We have recently extended this concept

to cancer or degenerative disease. Second,

of the targeted cell-cycle genes are down-

to the fruit fly Drosophila melanogaster,

it will support high-content screening in 2D

regulated in quiescent cells, which may

where it can be applied in conjunction with

and 3D cell culture, as well as small model

explain why certain cells in a tumor are

the powerful genetic toolkit available in this

organisms such as Drosophila, for drugs or

resistant to drug treatment. Therefore, we

model organism. Since its introduction in

druggable targets that switch cells into or out

plan to use our biosensor-based system to

2014 Fly-FUCCI has proven to be a reliable

of quiescence, or target them specifically for

screen for compounds specifically targeting

method for monitoring the proliferation

destruction.

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Big Data

Tools and services for ‘bespoke’ genome analysis | Petri Auvinen Predicting safe and novel uses of nanomaterials | Dario Greco Bioinformatics solutions for precision medicine | Liisa Holm Wasabi – web-based visualization and analysis of comparative sequence data | Ari Löytynoja

61


62


Petri Auvinen

Tools and services for ‘bespoke’ genome analysis Genome analysis requires a lot more than

This has been applied to the gut and skin

the bottleneck effect on speciation in a large

just DNA sequencing, even though efficient

microbiome in relation to disease, to food

mammal. By correlating patterns of genomic

and accurate high-throughput sequencing

spoilage, and to the analysis of environmental

variation with specific biological traits we

is a necessary starting point. Our group

samples, such as the microbial communities

hope to understand the molecular basis of

combines this ‘bedrock’ service with

in deep crystalline rocks.

adaptation to locally changing environments

comprehensive bioinformatic analyses, using

in a species under extreme threat.

tools also developed in-house for key steps

This varied portfolio has enabled us to

in the process, such as sequence alignment,

build up not only a state-of-the-art toolkit

Metagenomics is becoming an increasingly

annotation and protein-function prediction.

for genome analysis, but also the expert

important tool for detecting environmental

Throughout the work, we establish and

knowledge required to interface and team-

changes before they become irreversible.

maintain close interactions with the teams of

up with a broad spectrum of biologists, so

It will also have an increasingly important

biologists behind the various projects that we

as to extract information from genomes in

predictive role in medicine, as we learn more

undertake.

the ways most relevant to specific scientific

about the interaction between microbial

questions and real-world applications. This

communities and ‘host’ metabolism and

We have created our facility primarily to

has led to biologically significant findings. In

disease processes.

implement the assembly, annotation, and

the case of the Glanville fritillary butterfly,

functional and evolutionary analysis of

comparative genome analysis revealed a

In the future, the expertise we have acquired

large eukaryotic genomes, building on early

thus-far unique evolutionary feature in the

enables us to contemplate extending beyond

experience as part of a wide collaboration to

Lepidotera, not seen in other groups of

purely academic collaborations and launching

determine the genome sequence of barley.

animals such as mammals, whereby the

‘bespoke’ genome analysis as a commercial

The first two examples of species whose

order of genes along the chromosomes

service directly offered to animal or plant

genomes have been fully analysed by our

seems to be stable extending back at least

breeders, wildlife conservation agencies,

group are the Glanville fritillary butterfly

140 million years. The silver birch genome, on

healthcare providers and diverse other

(Melitaea cinxia; Nymphalidae) and the

the other hand, has been studied because of

organizations around the world. Thus, we are

silver birch (Betula pendula). Based on these

its economic importance in boreal forestry.

in the early phase of a search for investors

successes we are now involved in a number

Combined with appropriate field work, the

and developers to identify the most relevant

of other genome projects, notably the ringed

genome sequence opens up the possibility

markets and create a viable business out

seal, where our focus is the endangered

of identifying the molecular basis of growth

of what hitherto has been curiosity-driven

population unique to Lake Saimaa, and the

rate regulation, wood quality and pest-

research.

strawberry. In addition, we have developed

resistance. In the case of the Saimaa seal, the

extensive expertise in metagenomics.

emphasis is on conservation biology, and on

63


Dario Greco

Predicting safe and novel uses of nanomaterials Nanoparticles are molecules with at least one dimension smaller than 100 nm. Nanotechnology is categorized as one of the ‘Key Enabling Technologies’ in the EU’s current Research and Innovation program, Horizon 2020. The industry already employs more than 300,000 people in Europe, and the global market value of nanotechnology-enabled products is estimated at $2 trillion in 2015. These products are already present in our everyday life and new Engineered NanoMaterials (ENM) are continuously produced. However, the same physical, chemical, magnetic and electrical properties that make ENM extremely valuable, namely their high reactivity, are also regarded as a potential threat to human health and the environment. The possible risks associated with ENM are a major impediment to their adoption worldwide. Moreover, current safety testing of ENM is much too slow and laborious. This even applies to novel, controlled and safe applications of existing ENM in the field of nanomedicine. Thus, there is a tremendous need to accelerate hazard assessment and to predict the effects of ENM. On the other hand, some ENM effects could provide a great opportunity, for instance, in the contexts of innovative therapeutic protocols. Hence, it is essential to understand nano-bio interactions in depth and at multiple levels, in order to maximize ENM usability as well as safety.

The focus of our research group is

future regulatory applications. The respiratory

combinatorial use with drugs. Thus, we

predictive and systems nanotoxicology. We

system is the main exposure route for

aim not only to predict hazards, but also to

use cutting-edge genomic technologies,

humans, especially in work environments,

enhance existing therapeutic strategies.

artificial intelligence methods and systems

and is thus the context for one of our most

biology approaches to formulate predictive

important current research projects.

computational models of ENM toxicity and

64

Our long-term goals are (1) to develop procedures for rapid, large-scale hazard

biomedical usability. OMICs technologies

Our group is currently completing the

assessment of ENM; (2) to formulate

allow us to thoroughly characterize the

development of the first such computational

predictive algorithms capable of indicating

effects on human cells of exposure to ENM.

tool, INSIdE nano (Integrated Network of

the potential adverse effects of ENM, based

Novel bioinformatics methods are then

Systems bIology Effects of NANOmaterials),

just on the knowledge of their intrinsic

developed to integrate the experimentally

allowing systematic contextualization of

chemico-physical properties; (3) to produce

derived big data-sets, with the aim of

the mode of ENM action with the respect

computational tools for the systematic

characterizing the mode of action of ENM

to interactions with other chemicals,

prediction of ENM uses in broader biomedical

and revealing relevant biomarkers for use in

ability to cause diseases, and prospective

contexts.


Screenshot from our tool INSIdE nano tool depicting the network of interactions that Parkinson’s disease (PD, purple) have with chemicals (eg. the known dopaminergic neuron toxin MPTP, green), drugs (eg. Levodopa the preferred drug for the treatment of PD, red) and nanomaterials (blue). INSIdE nano is helping scientists and regulators to formulate hypotheses concerning the involvement of nanomaterials in pathogenesis of specific types of diseases (as in this example), or it could otherwise suggest a possible use of nanomaterials as a treatment for diseases.

65


The Overview Surgical Site infection

Infection information

Data and specimen collection • Wound biopsies • Swab Samples • Patient information

Functional analysis Infected surgical site Uninfected surgical site Burn wound

Metatranscriptomics sample processing • Homogenization • Extraction of total RNA • DNAse I digestion • Bead-based enrichment of bacterial RNA

• Species/strains • Antibiotic resistance • Virulence factors

Secondary analysis • Feature counting • ORF mapping • ORF calling

RNA-seq library preparation

Primary analysis

• Ribosome depletion

• rRNA removal

• Fragmentation

• Human mRNA removal

• Adapter ligation

• Quality trimming • Adapter removal

High-throughput sequencing

66

Data Generation


Liisa Holm

Bioinformatics solutions for precision medicine Post-operative complications caused

antibiotics in infection control, an extremely

relevant time frame. This is accomplished

by microbial pathogens in the wound

detrimental approach in the era of increasing

using in-house algorithms deployed in

occur in approximately 2% of all surgical

antimicrobial resistance. To facilitate more

superfast sequence database search servers.

interventions. In the US, they claim about

appropriate treatment and to minimize

Our approach belongs to a new generation

8,200 lives annually, and their societal cost is

the unnecessary use of broad-spectrum

of algorithms which is orders of magnitude

estimated at $1.6 billion.

antibiotics, it is imperative to develop novel

faster than BLAST, the industry standard.

techniques for identification of infectious

Importantly, these algorithms scale better

One of the most essential steps in the

pathogens and their virulence and antibiotic

because search time is independent of

diagnosis and management of surgical site

resistance determinants.

database size, enabling the processing

infections and other healthcare-associated

of larger quantities of data, against

infections is the prompt, accurate, and

Our project aims to advance our

exponentially growing databases, with the

reliable identification of the etiological

understanding of the etiology of surgical

same computer power.

agents. To date, however, pathogen

infections and develop cost-effective tools

detection from clinical samples has relied

for early recognition and customized

We have tested our computational pipeline

heavily on culture-based approaches and

treatment. As a pilot project in personalized

on test samples from patients and spiked

phylogenetic marker gene identification that

medicine, it combines top expertise in

controls, and shown that it identifies the

are narrow in scope and unreliable for the

microbiology, computational biology, surgery

potentially infectious agents.

characterization of many pathogens.

and clinical wound management. We employ cutting-edge DNA sequencing, healthcare

The project is a wide collaboration between

These limitations in conventional diagnostics

informatics, and bioinformatics algorithms

BI, clinical and non-clinical departments, and

techniques may compromise patient health

to define the relationship between infections

hospital services. As a spin-off it will establish

and delay the initiation of the correct

and the microbiota residing in surgical sites.

novel molecular tools and a tailored pipeline

antimicrobial therapy. The consequences

for analysing microbial community genomics

are a matter of life and death for individual

Our group coordinates and implements the

data. It thus has substantial potential for

patients, including the danger of long-term

computational aspects of the project. Our

improving the quality and cost-effectiveness

disability and decreased life quality. At the

expertise is in developing bioinformatics

of healthcare, and should be of interest to a

societal level, the deficiencies in pathogen

analysis pipelines that can annotate big

wide and global market.

recognition have contributed markedly to

data sets, as generated by metagenomics

the favoring of untargeted, broad-spectrum

(typically hundreds of gigabytes) in a clinically

67


Ari Löytynoja

Wasabi – Web-based visualization and analysis of comparative sequence data

Wasabi, developed by our team in BI, is a web-based

These can include:

environment for analysis and visualization of comparative

• in-house installation of Wasabi software

sequence data. The Wasabi analysis environment is versatile and adapts to diverse tasks in molecular genetics: for example, the phylogenetic profiling of human mutations, comparative analyses of microbial protein fragments,

with user training and support • extension of the Wasabi environment with custom analysis tools • construction of reference data sets

amplicon analyses of marker genes or epidemiological studies

(e.g. microbial protein families,

of pathogens. Wasabi runs inside a web browser and does

pathogen marker genes)

not require any installation: it can be immediately accessed

• embedded data browser,

and implemented, via wasabiapp.org. The Wasabi visualization

e.g. for scientific journals or

library is a self-contained package for web-based display of

sequence databases

sequence data. Wasabi windows can be embedded in webpages (see figure) and in web-applications, and allow live,

Wasabi data visualization is currently

browsable views of underlying data and fast data manipulation

integrated in the Ensembl genome

(translation, filtering, text search), performed locally within the

browser (ensembl.org). Our aspiration

browser. A prototype of embedded Wasabi visualization for

is to develop these extended services

scientific publishing is shown at wasabiapp.org/journal.

on a commercial basis, serving diverse business communities, such as publishers,

Wasabi represents a specific output from our work, serving

pharmaceutical companies, healthcare

the academic community. As such, the Wasabi environment

providers or public agencies.

is based on open-source software and wasabiapp.org is

68

available to all as a free service. However, for users requiring

For further details, see the videos and

strict confidentiality or having special needs, custom services

our publication describing Wasabi at

can also be provided.

wasabiapp.org/about.


Live, browsable Wasabi window embedded on a web-page, showing cetacean-specific changes in the haptoglobin gene, potentially preventing hypoxia-induced cell damage as an adaptation to deep diving.

69


Plants & Food

Molecular engineering the forest: rate and quality of wood formation | YrjÜ Helariutta Warming trees to combat global warming | Howy Jacobs Regulating gene expression and hormonal signaling to boost biomass production in trees | Ari-Pekka MähÜnen A tool for improving the efficiency and targeting of gene modifications in plants | Alan Schulman A robust resistance gene for yellow (stripe) rust | Alan Schulman

71


72


Yrjรถ Helariutta

Molecular engineering the forest: rate and quality of wood formation The aim of our research is to understand molecular mechanisms controlling plant vascular development, and use this knowledge to develop ways of enhancing economically useful traits in forest trees. The plant vasculature, which comprises the conducting tissues of phloem and xylem, provides structural support to the plant and enables the transport of water and sugars between shoot and root. Wood, the secondary xylem of plant stems, represents most of the carbohydrate biomass of the plant, and its composition is under genetic control. Our research thus has immense potential for the forest industry: the better we understand the molecular mechanisms controlling wood formation and composition, the easier it is to apply this knowledge. The molecular regulators that we have identified represent optimal target genes for tree breeding and forest biotechnology.

In our labs, we explore the molecular basis of

for various industrial purposes. Our current

Perspective: Our ultimate aim is to

vascular development in two complementary

focus is to modify lignocellulosic plant

engineer forest trees, so as to optimize

model systems: herbaceous Arabidopsis

biomass by adding callose to cellulose-rich

biomass production to yield high-value

thaliana and woody forest trees. Despite

cell walls. Both callose and cellulose are

products in the biorefineries of the future.

its small size, Arabidopsis produces wood

glucose polysaccharides, but with strikingly

and has emerged as a versatile model for

different structures: in contrast to cellulose,

plant vascular development. Based on our

callose does not form recalcitrant microfibril

Arabidopsis research, we have identified a

structures. By modifying the function

wealth of novel regulators of wood production.

of a callose synthase enzyme, we have

Using both transgenic and non-transgenic

already engineered transgenic plants for

gene editing methods, we can translate

overproduction of callose. Callose-enriched

this knowledge to modify the analogous

wood should require less energy to liberate

developmental processes in a tree trunk.

simple sugars from cell walls and thus significantly reduce the costs of industrial

Besides boosting biomass production in

processes that use the released sugars, for

forest trees, we aim to optimize its properties

example, to yield biofuels.

73


Howy Jacobs

Warming trees to combat global warming The Boreal Forest is one of the world’s major carbon sinks. Accelerating its growth or extending its range would contribute significantly to decreasing net CO2 emissions. When combined with sustainable forestry, it could result in increased production of renewable fuels and many other products that today are sourced primarily from fossil materials.

We are working on a strategy to address

Extending this concept to tree species

Our research group is now looking for

the challenge of accelerating tree growth,

means that we can realistically contemplate

investors and commercial partners

by taking advantage of a natural system

engineering trees to over-express AOX,

to accelerate this project, developing

present in all plants, the alternative oxidase,

thus generating heat that will promote their

and licensing this technology for use in

AOX. AOX buffers stress and overload in the

growth at sub-optimal temperatures, such

commercial forestry.

mitochondrial energy system, by serving as

as those encountered globally across the

a by-pass that conducts electrons released

far north, where the majority of the world’s

by biological oxidations directly to oxygen.

remaining forests are located.

In so doing, it releases energy as heat,

74

rather than as ATP. This pathway is used

Previous studies have shown that the growth

naturally by some plants to generate heat,

of the major tree species in the Boreal Forest,

for example, by arum lilies to volatilize insect

notably Scots Pine, Norway Spruce and Silver

attractants. AOX activity is induced under

Birch, is strongly influenced by temperature

extreme cold in many plants, and may play

during the growth season, and this effect

a role in resistance to freezing. However,

is most pronounced at environmental

in the model plant species Arabidopsis,

temperatures encountered near the northern

engineering AOX over-expression has already

limits of the range. Ironically, global warming

been shown to promote growth of the plant

itself has already had a demonstrable effect

even at the more temperate condition of 15

on tree growth in Finland. The advent of

°C. In effect, some of the energy captured

gene-editing technology now makes it

from sunlight by photosynthesis is being

theoretically feasible to engineer AOX over-

‘wasted’ to produce heat. But the net effect

expression in commercial trees, promoting

on biomass production is strongly positive,

greatly accelerated growth, increased carbon

because of the temperature-dependence of

capture and, in the longer term, increased

the chemistry of biosynthesis.

production of renewable raw materials.


75


Ari-Pekka MähÜnen

Regulating gene expression and hormonal signaling to boost biomass production in trees

Wood (or xylem) constitutes a large fraction

translate this knowledge to tree species,

our specific knowledge of the mechanisms

of global biomass. It is produced in plants

where it could have profound economic and

promoting cambial development, will enable

by a tissue known as the vascular cambium,

environmental benefits.

us to breed birch varieties with increased

the cylindrical secondary meristem located

biomass production or altered wood quality

in stems and roots, that serves as a stem-cell

Our next step in this project is to overexpress

characteristics much more rapidly than any

compartment for producing the adjacent

the Arabidopsis cambial factors in the

classical selection-based techniques.

cell layers. Cambium activity is particularly

cambium of poplar, and select lines with

important in tree trunks. Understanding the

increased secondary growth and production

We plan also to initiate discussion with

molecular regulatory mechanisms directing

of lignocellulosic biomass. This approach

forestry companies, in order to collaborate

cambial development brings us powerful tools

will serve as a proof-of-concept step to

on the use of poplar lines already engineered

to enhance the biomass production of trees,

show the potential of these factors to breed

for overexpression of cambial factors, or to

formed as the lignocellulosic carbohydrates

commercially important tree species.

generate new overexpression lines in other

that we recognize as wood. Work by us

76

economically important species cultivated

and others has revealed a central role for

In Finland, silver birch (Betula pendula) has

globally, such as Eucalyptus.

the plant hormone cytokinin in promoting

emerged as an intensively studied tree

cambial development in the model plant

species because of its suitability for genetic

Our long-term goal is to use the information

species Arabidopsis thaliana and in the

breeding programs, plus its economic

provided by our studies in model species

poplar (Populus tremula x tremuloides).

importance in Finland and for the entire

to generate tree varieties with enhanced

Following up our earlier studies on cytokinin

boreal forest. Using available genome editing

production of lignocellulosic biomass, or

and the cambium, my group has identified

techniques (CRISPR/Cas9) we will next target

improved wood quality characteristics. This

downstream factors of cytokinin signaling

birch homologues of the Arabidopsis cambial

has the potential to revitalize forestry in

whose function is specifically to regulate

genes, to generate both gain-of-function

Finland and elsewhere, helping to address the

cambial development. Overexpression of

and loss-of-function mutations predicted to

challenges of climate change and the need to

these factors in Arabidopsis resulted in

enhance the response to cytokinin signaling.

switch to renewable, biologically sourced raw

increased secondary growth. Our aim is to

Genome editing techniques, combined with

materials.


77


78


Alan Schulman

A tool for improving the efficiency and targeting of gene modifications in plants Production of transgenic plants for

A solution to this problem is provided by

therapy. Investment is now needed to develop

agriculture is increasingly important

retrotransposons and retroviruses, nature’s

tethered integrases and transformation

worldwide; 182 million hectares of GM

genetic engineers, which insert their own

complexes for cereal genome modification,

crops were planted in 2014, with an annual

genomes into the DNA of the cell as part of

extending this proof-of-concept to BARE.

increase of 3-4 %. Soybean (79% GM), maize

their natural life cycle. Retrotransposons are

The resulting technology would offer many

(32%), cotton (70%) and rapeseed (24%)

abundant, non-infectious components of all

benefits. It could be used as a proprietary

have the greatest proportion of total area

plant genomes, carrying out their transposition

system for in-house transformation, offered

in GM varieties. However, whilst wheat and

using an enzyme called integrase. We have

as a service for plant breeding companies,

barley are both in the world’s top four cereal

studied the retrotransposon BARE, found in

or licensed further. It could in principle be

crops, no GM barley or wheat is grown. One

both barley and wheat, as well as in related

tailored for targeted integration of transgenes

limitation is that only a few varieties are

cereals, for over 25 years, accruing a large

in any crop species where BARE integrase

transformable; frequencies above 25% are

body of knowledge of its life-cycle and

will function. Because integrases are highly

seldom achieved in barley, and are far lower

integrase function.

conserved, this is likely to cover a wide

in wheat. Another, more general problem is

species spectrum, certainly including the

the lack of a targeting mechanism to direct

We propose to develop BARE integrase as a

Triticeae (wheat, barley, rye, timothy) and

the transgene to a particular site in the

commercially viable transformation vector for

Pooideae (e.g. oats).

genome. With current methods, a transgene

the targeting of transgenes to specific locations

may be integrated anywhere. Given the

in cereal genomes. Although the integrase

Competing technologies are problematic.

high proportion of heterochromatin in

normally inserts its substrate semi-randomly

Homologous recombination for specific

barley, wheat and other large genomes,

throughout the genome, specificity can be

targeting is possible, but is extremely inefficient

most insertions occur in areas with poor

achieved by tethering the integrase to another

and needs selection. Specific removal of

expression. As a result, many transgenic lines

protein with DNA or protein-binding capacity.

genes has been reported with the piggyBac

must be produced in order to recover just

For example, linking integrase to a particular

insect transposon. The CRISPR/Cas9 system

one with suitable expression levels. There

transcription factor will lead to integration

is becoming widely used for site-specific

is also the issue of silencing due to position

wherever in the genome that transcription

mutagenesis, but still depends on homologous

effects, which can occur even if transgene

factor binds. Proof-of-concept has been

recombination for targeted insertion. Thus,

expression is initially satisfactory.

achieved using retroviral (e.g. HIV-1) integrases

tethered BARE integrase should have a secure

to create targeted integrations for gene

place in a potentially vast market.

79


Alan Schulman

A robust resistance gene for yellow (stripe) rust

Wheat is the world’s second most important

potential solution. Yr15, a major gene located

1) direct transfer of the gene without the

grain crop, planted on 219 million Ha

on chromosome 1BS of T. dicoccoides, was

problem of linkage drag; 2) editing of the gene

and yielding 716 million tons worldwide

previously reported to confer resistance to a

for introducing new variants to overcome

(FAOSTAT, 2013). Wheat supply and demand

broad spectrum of stripe-rust isolates, at both

any emerging resistance; 3) potential design

has seesawed over recent years, with eight

seedling and adult plant stages. Introgressions

of new resistance genes for other crops and

seasons of surpluses and 12 of deficits

of Yr15 into cultivated T. aestivum (bread

fungal diseases or direct use of Yr15 in barley

over the last two decades. As witnessed

wheat) and T. durum (pasta wheat) have been

and related cereals.

by the North African food riots of 2008,

widely used since the 1980s, but remain

political stability is closely linked to wheat

problematic, due largely to associated “linkage

The confirmed Yr15 gene can be made

prices, which are in turn affected by wheat

drag� of undesirable flanking genes.

available on a commercial basis for in-house

production. The yellow (or stripe) rust disease

80

or licensed use by plant breeding companies.

is today one of the most signficant threats to

We have been working on a long-term project

Its benefits will include the development not

wheat production. It is caused by the fungus

to clone Yr15, using a variety of genetic and

only of improved disease-resistant bread-

Puccinia striiformis f. sp. tritici, the spores

genomic methods. We currently have a

and durum-wheat varieties, but of fungal

of which can be wind-dispersed over long

candidate gene identified and under testing

pathogen-resistant strains of other crops.

distances, even thousands of kilometers.

for verification. The candidate gene is not a

The Yr15 gene has no current competition,

While the best strategy to overcome

typical NBS-LRR type resistance gene, which

as it is the only gene that confers sustained

the disease is to breed resistant wheat,

explains why the resistance conferred by Yr15

resistance to all known yellow-rust isolates.

the pathogen has repeatedly developed

has, unusually, not been broken in the 30

Other resistance genes tend to lose

immunity against available resistance genes

years since it was first used. Final confirmation

effectiveness over time, as the fungal strains

by evolving increased virulence.

of the Yr15 gene identity will require a

evolve. Thus, Yr15 can provide a unique and

combination of knockout and gain-of-function

robust answer to a major scourge of world

Wild emmer wheat, Triticum dicoccoides,

strategies. Knowledge of the molecular details

agriculture.

is an important source for novel yellow-

of the resistance gene (sequence, control

rust resistance (Yr) genes, which provide a

of expression, natural variation) will enable:


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Profile for Z-Factory

Frontier Biotech from Finland 2016  

Biotech Plaza - 80 sivuinen esite.

Frontier Biotech from Finland 2016  

Biotech Plaza - 80 sivuinen esite.

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