Some thoughts on systems biology
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Some thoughts on systems biology Harvey Rubin, MD, PhD [email protected] The four questions for systems biology. Can biological systems operationalize certain aspects of cyber systems so that we can understand and design advanced biological systems ?

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Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Some thoughts on systems biology

Harvey Rubin, MD, PhD

[email protected]


The four questions for systems biology

The four questions for systems biology

  • Can biological systems operationalize certain aspects of cyber systems so that we can understand and design advanced biological systems?

    2. Can biological systems operationalize certain aspects of cyber systems so that we can understand and design advanced cyber systems?

    3. Can cyber systems operationalize certain aspects of biological systems so that we can understand and design advanced biological systems?

    4. Can cyber systems operationalize certain aspects of biological systems so that we can understand and design advanced cyber systems?


Cyber bio comparisons on the totally arbitrary and arguable scale of 1 5

Cyber-Bio comparisons: on the totally arbitrary and arguable scale of 1-5

CyberBio

Logic operations51

Programmable52

Parallel processing35

Standardization53

Abstraction52

Modularity55

Predictability of part53

Predictability of part in system42

Stable/durable in the natural environment43

Stable/durable under stress and attack24

Energy efficiency25

Logically reversible24

Thermodynamically reversible24

Scalable33

Evolvable15

Self learning15

Self repair15

Self correcting15

Self assembly 15

Self-Replicating(hardware)05

Richness of user interface24

Multi-agent communication34

Aggregate data and predict outcomes0-14

Solve the “inverse problem”0-15

Impact on society0-45


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

1. Can biological systems operationalize certain aspects of cyber systems so that we can understand and design advanced biological systems?

Logic operations51

Programmable52

Parallel processing35

Standardization53

Abstraction52

Modularity55

Predictability of parts53

Predictability of parts in system42

Stable/durable in the natural environment44

Stable/durable under stress and attack24

individuals

societies and

cultures


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Answer to Question 1 –YES

this is predominantly in the world of molecular and synthetic biology

  • Cell cycle counter and cell division reporter

  • Control metabolic pathways and switches

  • Regulate intracellular communications

  • Microbial fuel cells

  • New therapies

  • Biological sensors

Roger Kornberg

Arthur Kornberg

Andrew Fire

Craig Mello


Protein synthesis

Protein synthesis


Systems synthetic biology

Systems-synthetic biology

  • synthetic biology seeks both to employ nonnatural molecules to mimic biological behavior and to assemble well-characterized biomolecular components into circuits that perform prescribed functions.

  • potential to expand our understanding of biomolecular networks and enhance our ability to engineer novel cellular behavior.

  • most efforts have focused on engineering gene circuits that rely on protein-DNA interactions to control transcription


Rna molecules are malleable and attractive molecule that can drive programmable functions

RNA molecules are malleable and attractive molecule that can drive programmable functions

  • RNA molecules, adopt complex structures

  • can be generated from potentially all possible sequence combinations

  • leads to diverse secondary structure and function

  • causal relationship between sequence, structure and function significantly affects the interaction of RNA molecules with proteins, metabolites and other nucleic acids


Programmable functions are the effects of proteins understand protein synthesis

Programmable functions are the effects of proteins: understand protein synthesis

  • requires a series of catalytic and regulatory steps involving key cellular machinery.

  • several factors affect translation initiation, including ribosomal recognition of the mRNA ribosome binding site (RBS) and the start codon

  • regulate bacterial gene expression by interfering with ribosomal docking at the RBS

  • create a modular post-transcriptional regulation system that could be integrated into biological networks and implemented with any promoter or gene


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Example: an engineered Ribo-regulator


Suppose you can synthesize almost anything what could would you do

suppose you can synthesize almost anything…What could/would you do?

“The 1918 virus and recombinant

H1N1 influenza viruses were generated using the previously described reverse genetics system (8, 14). All viruses containing one or more gene segments from the 1918 influenza virus were

generated and handled under high-containment biosafety level 3 enhanced (BSL3) laboratory conditions in accordance with guidelines of the National Institutes of Health and the Centers for Disease Control and Prevention (15).”


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

“1918 Flu and Responsible Science”

“I firmly believe that allowing the publication of this

information was the correct decision in terms of both national security and public health.”

Science Editorial Vol. 310, 7 October 2005 Philip A. Sharp


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

“The 1918 flu genome: Recipe for Destruction”

“This is extremely foolish. The genome is essentially

the design of a weapon of mass destruction.”

New York Times Op-Ed

October 17, 2005

Ray Kurzweil and Bill Joy


Mr president i feel i have blood on my hands

“Mr. President, I feel I have blood on my hands”

“I don’t want to see

that son of a bitch

in this office ever again.”


Systems biologists are our hands bloody

Systems biologists- are our hands bloody?

Demonstrate how to render human or animal vaccines ineffective

Confer resistance to therapeutically useful antibiotics or antiviral agents for humans, animals, or crops

Enhance the virulence of human, animal, or plant pathogens, or make nonpathogens virulent

Increase the transmissibility of pathogens

Alter the host range of pathogens

Enable the evasion of diagnostic or detection methods

Enable the weaponization of biological agents or toxins

Generate novel pathogens or toxins, or reconstitute an eradicated pathogen


Nrc report on dual use research

NRC Report on Dual Use Research

Report of the National Research Council of the National Academies:

“Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma” (October 2003)


Life sciences need for biosecurity

Life Sciences: Need for Biosecurity

  • “Dual use” potential of certain life sciences research requires consideration of biosecurity measures

  • Goal (and challenge) is to enhance biosecurity protections for life sciences research while ensuring that any impact to the free flow of scientific inquiry is minimized.


National science advisory board on biosecurity

National Science Advisory Board on Biosecurity

http://www.biosecurityboard.gov


National science advisory board for biosecurity nsabb

National Science Advisory Board for Biosecurity (NSABB)

The NSABB is established to provide advice to federal departments and agencies on ways to minimize the possibility that knowledge and technologies emanating from vitally important biological research will be misused to threaten public health or national security.

  • Advisory to the Secretary of Health and Human Services, Director of National Institutes of Health, and heads of all US federal departments and agencies that conduct or support life science research

  • Will recommend specific strategies for efficient and effective oversight of US federally conducted or supported dual use biological research


Nsabb ex officios

Exec. Office of the President

Department of Health and Human Services

Department of Energy

Department of Homeland Security

Department of Veteran’s Affairs

Department of Defense

Environmental Protection Agency

United States Department of Agriculture

Department of Interior

National Sciences Foundation

Department of Justice

Department of State

Department of Commerce

National Aeronautics and Space Administration

Intelligence community

NSABB ex officios


Criteria for dur emerging concepts

Criteria for DUR: Emerging Concepts

Research:

With agents that possess a high biological threat/risk potential

That could increase the potential of an agent to cause harm

Apply Criteria Developed from these Categories

Dual Use Research

That could enhance susceptibility of host populations to harm

That yields enabling technologies or facilitating information

That may be misused to pose a biologic threat to public health and/or national security


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

2. Can biological systems operationalize certain aspects of cyber systems so that we can understand and design advanced cyber systems?

CyberBio

Logic operations51

Programmable52

Parallel processing35

Len Adelman DNA computation papers—highly parallel, solve NP problems


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Physical Limitations of DNA Computing

Directed Hamiltonian path problem

25 nodes…..

1 kilogram of DNA needed

70 nodes…..

1000 kilograms of DNA needed

Decryption

101233 strands of DNA

at 0.17 uM------->101216 liters!

From Cox, Cohen,& Ellington


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Adleman reported in a meeting that

he solved a 20 variable SAT problem using DNA

“It is not remarkable that the bear dances well--

It is that the bear dances at all”


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Not particularly interested in dancing bears, we decided to see if DNA computing had anything to say about some of the fundamental limits of computation

CyberBio

Energy efficiency25

Logically reversible24

Thermodynamically reversible24

The Fundamental Physical Limits of Computation

What constraints govern the physical process of computing? Is aminimum amount of energy required, for example, per logic step?There seems to be no minimum., but some other questions are open

by Charles H. Bennett and Rolf Landauer

Scientific American253(1):48-56 (July, 1985).


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

A Fredkin Gate: Logically reversible with no energy limit on the computation

CAB is a piece of DNA that we can synthesize


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

a NAND gate


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Why reversible?

Minimal energy expense

Detection and correction of intrusion

Error checking by reversing computation

to recreate inputs

Bidirectional debugging


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

In principle it can take minimal energy to go through a biochemical gate

DNAn + dNTP DNAn+1 + PPi

D G = kt ln[dNTP/PPi]

If dNTPs are just 1% over the equilibrium value:

D G = kt ln[10.1/10] or about 0.01kT

a modification of an idea in Bennett and Landaur’s Sci. Am paper—suggested using RNA


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

We synthesized the oligonucleotides and ran the reactions

Klein, JP., Leete, TH. & Rubin H. A Biomolecular Implementation of Logically Reversible Computation with Minimal Energy Dissipation. BioSystems 52, 15-23, 1999.


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

The gate works in the lab


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

How fast is the gate?

t1/2 annealing: 3 sec.

DNA polymerization rate: 15 bases/sec

For 60 bases pair input: 10 sec

  • Can biological systems operationalize certain aspects of cyber systems so that we can understand and design advanced cyber systems?

  • ---NO


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

3. Can cyber systems operationalize certain aspects of biological systems so that we can understand and design advanced biological systems?

  • Nano-bio

  • Medical devices

  • Lab on a chip

  • NSF workshop on high confidence medical devices and software systems last year

  • Subject of Tele-Physical services and applications working group at this meeting

  • > $3 billion invested already

2007 NSTI Nanotechnology Conference and Trade Show – May 2007 - Santa Clara

Life Sciences & Medicine

Bio-nano Materials & Tissues

Bio Sensors & Diagnostics

Biomarkers & Nanoparticles

Cancer Nanotechnology

Cellular & Molecular Dynamics

Drug Delivery & Therapeutics

Imaging

Nano Medicine

Nanotech to Neurology

Answer to Question 3--YES


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

CyberBio

Evolvable15Self learning15Self repair15Self correcting15Self assembly 15Self-Replicating (hardware)05Richness of user interface24

Multi-agent communication34

Aggregate data and predict outcomes0-14

Solve the “inverse problem”0-15

Impact on society0-45

4. Can cyber systems operationalize certain aspects of biological systems so that we can understand and design advanced cyber systems?


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Can cyber systems operationalize certain aspects of biological systems so that we can understand and design advanced cyber systems?

examples abound from molecular level to societal level

  • Persistence in bacteria as hedge strategy against attack

  • Quorum sensing

  • Cellular metabolism- metabolome:metabolic flux models

    • supply chain

  • Swarm behavior

    • Autonomous mobile robots

  • Markets

    • Data aggregation

    • Event prediction


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Problem to solve: tuberculosis

TB infection is spreading at the rate of one person per second.

The disease kills more young people and adults than any other infectious disease and is the world's biggest killer of women.

Each year, an estimated eight million to 10 million people contract the disease and about two million people die from it.

An estimated 33% of the 40 million people living with HIV/AIDS worldwide are co-infected with TB.

Without treatment, 90% of people living with HIV/AIDS die within months of contracting TB.

The majority of people who are co-infected with both diseases live in sub-Saharan Africa.


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Here’s one of the big problems for tuberculosis as well as many other biological systems……

PERSISTERS


Bio systems under potential attack persistence in bacteria

Bio-systems under potential attackPersistence in bacteria

  • microorganisms often encounter an environment with limited nutrients or certain other stress related stimuli

  • they enter a dramatically slowed growth state until a new equilibrium is established


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

“However, no further additional bactericidal activity was found during further incubation with isoniazid alone or when gatifloxacin was added to either isoniazid or rifampin. This suggested that the stationary- phase culture contained a mixture of occasionally dividing bacilli that were killed during the first 2 days and true static persisters in the residual population that mimicked those in human lesions.”


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

The bug must have a mechanism(s) to sense and respond to hard times…...sense the environment and couple inhibition of transcription to inhibition of translation


Stringent response system in mtb

Stringent Response System in Mtb

  • Regulation of a key component of the pathogenesis of Mycobacterium tuberculosis is determined by the ability of the bacterium to sense and respond to adverse growth conditions …...couple inhibition of transcription to inhibition of translation

  • Deletion of this response will disable the bacterium—keep metabolism going to kill the cells in the presence of antibiotics!

  • Insertion of this response will enable an organism to maintain viability under stress conditions

  • The survival response comprises the interplay of a complex network of genes and proteins


Two opposing rel mtb activities

Two opposing RelMtb activities

1) pppGpp synthesis:

p-p-p-G + p-p-p-A p-p-p-G-p-p + p-A

GTP +ATPG5 + AMP

2) pppGpp hydrolysis:

p-p-p-G-p-pPPi + p-p-p-G

pppGpp alters RNAP kinetics and mediates the transcriptional response to environmental conditions to which Mtb is exposed


Systems biology molecular components of persistence in bacteria

Systems biology: molecular components of persistence in bacteria


Persistence in bacteria

Persistence in bacteria

Kill curves in the presence of ampicillin

E. COLI PERSISTENCE LINKED TO (p)ppGpp BY A MIXED STOCHASTIC AND DETERMINISTIC MECHANISM

Halász, Buckstein, Imieliński, Marjanovich, Teh, Kumar, Rubin


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

(B) Histograms obtained by sampling the growth rates of one single-cell simulation over approximately 1000 hours. The thin line marked "(p)ppGpp knockout 2" corresponds to a shorter sampling period which does not include a large shutdown event.

(C) Kill curves derived from the growth rate histograms. Both versions of the knockout exhibit fewer persisters.


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Lungs from mice infected with wild type MTb

Lungs from mice infected with Rel KO strain

Lungs from mice infected with Rel KO strain

complemented with plasmind containing rel

Spleens from mice infected with WT-KO—KO + comp


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

The bug must have a mechanism to make energy in the form of ATP—the role of the respiratory chain


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

TUBERCULOSIS — METABOLISM AND RESPIRATION IN THE ABSENCE OF GROWTH

Helena I. M. Boshoff and Clifton E. Barry, 3rd

NATURE REVIEWS | MICROBIOLOGY VOLUME 3 | JANUARY 2005 |


Some thoughts on systems biology harvey rubin md phd rubinh maild upenn

Research program:Can cyber systems operationalize certain aspects of biological systems so that we can understand and design advanced cyber systems?

CyberBio

Evolvable15Self learning15Self repair15Self correcting15Self assembly 15Self-Replicating (hardware)05Richness of user interface24

Multi-agent communication34

Aggregate data and predict outcomes0-14

Solve the “inverse problem”0-15

Impact on society0-45


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