Synthetic Biology: Topics in Health and Therapeutics Tumor Killing

8/14/2019 Synthetic Biology: Topics in Health and Therapeutics Tumor Killing

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Synthetic Biology:

Topics in health and therapeutics

Images courtesy of http://pathport.vbi.vt.edu/pathinfo/pathogens/E.coli_O157H7.html

Anthropology 112

Fall 20o7

Aaron Ravel, Stefanie Graeter

Lynn Wang, Paul Yousefi, Daisyca Woe

Tumor

Killing

Bacteria


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The Goals of the Testbeds are:

demonstrate the utility of synthetic biology

Integration of thrusts: Parts, Devices, Chassis

develop the foundational infrastructure that is

needed to make routine the design and constructionof any engineered biological system

Develop the BioBricks Open Source Registry


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(http://www.synberc.org/testbed_integration.html)


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The design of parts, devices, and chassis

throughout the entire process

Registration of these components in the

registry for use by other researchers

Use of abstraction hierarchy:biology can be engineered like a machine


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Is building a therapeutic microbe really like designing a machine?


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Start with an organism thatpossesses the desired qualities

Edit or tweak by removing oradding genes

Add genes that will provide desiredbehaviors in a controlled manner

Start with a well-characterized,model organism


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How is cancer therapy research on

Clostridium a top-down approach?


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Gram +, bacillus,sporulating, obligateanaerobes

Only a few species arepathogenic to humans.

Many release (entero)toxins

capable of lysing, orpopping, eukaryotic cells.

Images courtesy of Kominsky, Scott L., et al. Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight

junction proteins claudin 3 and 4.American Journal of Pathology. 4(2004): 1627-1633.

And http://textbookofbacteriology.net/clostridia.html


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Growth control and

safety Immune evasion Therapeutics

desired behaviors?


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Desired behavior:growth is kept in-check

Clostridium spores ONLY germinate in low oxygenenvironments (e.g. tumors).

E. coliK12 will be engineered to lack ion transportsystems.


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Clostridium was not cleared by the immune systemin tests.

E. coliK12 will have modifiedLPS and addition of O-antigen.

Desired behavior: avoid detection by the immune

system


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Desired behavior: ability to kill tumor cells

efficiently

Clostridium naturally releases enterotoxins capableof lysing tumor cells.

Recombinant strains: enhanced killing.

E. colimust be programmed to kill.


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Clostridium E. coli K12

Injection Injection

Growth control:innate

Growth control:programmed

Immune evasion:

innate

Immune evasion:

programmed

Therapeutics:

innate andprogrammed

Therapeutics:

programmed


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Theory differs from practice

Time in lab often spent synchronizing components

BioBricks Registry does not account for dynamicnature

of living systems

Will the Trial and Error processes be shared as well?


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Chemotherapy:

the use of chemical agents to kill cancer cellsand prevent them from growing

Radiotherapy:medical use of x-rays to fight and control

malignant cells in cancer treatment


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Advantages

Disadvantages


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Why is TKB soappealing?


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Less invasive.More direct and site-specific.


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Western medicinaltreatment strategies

Pharmacopoeia of

small molecules

Previous uses ofbacteria in medicine

Bladder Cancer andBacillus Calmette-Guerin (BCG)


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Oragenics and Osel: Dental cavity

protection, UTI

treatment - a lifetimewith microbes

Resistance?

Mutation?Safety Concerns


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Irritable BowelSyndrome

Selective secretion ofcytokines

Some recombinant

gene technology

usedModification of

existing bio-systems


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Differences between TKB and preexisting

bacterial therapies

Direction of approach (top-down, bottom-up)Listeria monocytogenes, eliciting of innate

immune response (Cerus Inc., Concord)

Salmonella typhimurium, inherent localizationwith added toxicity (Vion Pharmaceuticals, NewHaven)


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Problems as Anderson and Synthetic Bio seethemSafety concerns

Problems of technical mastery

FDA Concerns

Safety, as wellCost benefit analysis

Cancer ideal, potential benefit high and cost low


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FDA, regulatorybodies, involvedscientist

Only real concern

Beyond safety, humanpractices

Dual use, who getsaccess, will this allowflourishing?


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Dual Use: Alternate functions of the project (its parts,devices, chassis) that pose threateningconsequences.

Primary dual use concerns for the TKB project :

Designed to evade the immune system

Designed to kill cells

Designed to be modular and easily augmentable forother synthetic biology projects


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Is there a possibility for DNAmutations to affect theProgrammed functionsof TKB?

The current statistic thrownaround is a 10^-6 chance perbase pair of mutation (A veryreal possibility).

Solution: Integrate multiple fail-safe devicesinto the project that will terminate the TKB cellnot only after it reaches the tumor cell, but alsoif a mutation is present.


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Currently the TKB project is at the crux ofpassing from one stage of development to thenext (from chassis development to animal

testing stages). The schedule for the litigationto clear up and animal testing to begin is mid-January.

Even with this progress, the project is still inearly stages of development, and a definitetimeline is still unavailable.


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Even though the project is still in such

early developmental stages, why call it Tumor

Killing Bacteria versus fundamentaltechnologies development?

In order to establish interest both from fundingsources (i.e. federal or venture capitalists) aswell as from prospective researchers entering

the field.


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The access to treatment of cancer from acompleted TKB project will be significantlylimited by the cost of the cells once they areready for distribution.

The cost of the cells will be a factor not of

producing the drug, but of both the licensingfees and the cost of clinical trials for FDAapproval, as well as the profit margin thelicensed companies wish to achieve.


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Any Questions?

Synthetic Biology: Topics in Health and Therapeutics Tumor Killing

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