|
|
| (One intermediate revision by the same user not shown) |
| Line 1: |
Line 1: |
| − | {{Northeastern_Boston/CSS}}
| |
| − | {{Northeastern_Boston/Javascript}}
| |
| − | <html>
| |
| − | <script src="//use.typekit.net/jdw6eyl.js"></script>
| |
| − | <script>try{Typekit.load();}catch(e){}</script>
| |
| − | <body>
| |
| − | <div class='wrapper'>
| |
| − | <div id='sidebar'>
| |
| − | <div id='bar_title' class='title'><a href="https://2015.igem.org/Team:Northeastern_Boston" style="font-color:white">
| |
| − | Northeastern</a>
| |
| − | </div>
| |
| − | <ul class='nav'>
| |
| − | <li>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston">Home</a>
| |
| − | </li>
| |
| − | <li>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/team">Team</a>
| |
| − | </li>
| |
| − | <li>
| |
| − | <a class='active'>Project</a>
| |
| − | </li>
| |
| − | <div class='sub-nav__container'>
| |
| − | <li class='sub-nav__parent'>
| |
| − | <a>Parts</a>
| |
| − | </li>
| |
| − | <div class='sub-nav__children hidden'>
| |
| − | <li class='sub-nav__child'>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/BasicParts">Basic & Composite</a>
| |
| − | </li>
| |
| − | <li class='sub-nav__child'>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/ExpressionPlasmid">Expression Plasmid</a>
| |
| − | </li>
| |
| − | </div>
| |
| − | </div>
| |
| − | <div class='sub-nav__container'>
| |
| − | <li class='sub-nav__parent'>
| |
| − | <a>Notebook</a>
| |
| − | </li>
| |
| − | <div class='sub-nav__children hidden'>
| |
| − | <li class='sub-nav__child'>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/notebook">Protocols</a>
| |
| − | </li>
| |
| − | <li class='sub-nav__child'>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/Workflow">Workflow</a>
| |
| − | </li>
| |
| − | </div>
| |
| − | </div>
| |
| − | <li>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/Attributions">Attributions</a>
| |
| − | </li>
| |
| | | | |
| − | <div class='sub-nav__container'>
| |
| − | <li class='sub-nav__parent'>
| |
| − | <a>Human Practices</a>
| |
| − | </li>
| |
| − | <div class='sub-nav__children hidden'>
| |
| − | <li class='sub-nav__child'>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/HumanPractices">Outreach</a>
| |
| − | </li>
| |
| − | <li class='sub-nav__child'>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/Open_Source">Open Source</a>
| |
| − | </li>
| |
| − | <li class='sub-nav__child'>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/Jurassic_Wet_Lab">Jurassic Wet Lab</a>
| |
| − | </li>
| |
| − | </div>
| |
| − | </div>
| |
| − | <li>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/safety">Safety</a>
| |
| − | </li>
| |
| − |
| |
| − | <li>
| |
| − | <a href="https://2015.igem.org/Team:Northeastern_Boston/measurement">Measurement</a>
| |
| − | </li>
| |
| − |
| |
| − | </ul>
| |
| − | </div>
| |
| − | <div class='content'>
| |
| − | <div id='page-header__notebook' class='page-header'>
| |
| − | <h1 class="page-header__title" align="left" style="border-width:0">OUR PROJECT</h1>
| |
| − | </div>
| |
| − | <div class='Notebook'>
| |
| − |
| |
| − | <div class="minimal-dropdown__container">
| |
| − | <div class="minimal-dropdown__header">
| |
| − | <h2 class="minimal-dropdown__title">Overview</h2>
| |
| − | <a class='minimal-dropdown__arrow'></a>
| |
| − | </div>
| |
| − | <div class="minimal-dropdown__content hidden">
| |
| − | <p><i>"Dr. George D. Yancopoulos, chief scientific officer of Regeneron,
| |
| − | said the crisis had pointed up shortcomings in biodefense. “Nobody is
| |
| − | really prepared,” he said. “Nobody in the world has rapid response
| |
| − | capabilities.”</i>—New York Times, January 2015</p>
| |
| − |
| |
| − | <p>Humans need improved methods for making therapeutic antibodies.
| |
| − | Producing these complex proteins is hard but important; the 2014 Ebola
| |
| − | Outbreak illustrates the urgency. In response, we propose the use of
| |
| − | microalgae as a widescale antibody production platform. Microalgae have
| |
| − | all the benefits of higher-level plants but scale faster and are easier
| |
| − | to process. Furthermore, from a holistic point of view, microalgae are an
| |
| − | ideal chassis; their primary carbon source is CO<sub>2</sub> and they are
| |
| − | unlikely to harbor mammalian pathogens.</p>
| |
| − | </div>
| |
| − | </div>
| |
| − |
| |
| − | <div class="minimal-dropdown__container">
| |
| − | <div class="minimal-dropdown__header">
| |
| − | <h2 class="minimal-dropdown__title">The Need</h2>
| |
| − | <a class='minimal-dropdown__arrow'></a>
| |
| − | </div>
| |
| − | <div class="minimal-dropdown__content hidden">
| |
| − |
| |
| − | <p><i>"I rate the chance of a nuclear war within my lifetime as being
| |
| − | fairly low. I rate the chance of a widespread epidemic, far worse than
| |
| − | Ebola, in my lifetime, as well over 50 percent."</i> —Bill
| |
| − | Gates</p><img id="outbreakgif" src=
| |
| − | "http://giant.gfycat.com/SaltyElectricAmazonparrot.gif" style=
| |
| − | "width:100%">
| |
| − |
| |
| − | <p id="outbreakgifdesc"></p>Epidemic spread modeling by Brockmann's group
| |
| − | at Humbolt University. (http://rocs.hu-berlin.de/). This model shows the
| |
| − | spread of a theoretical outbreak of a particularly contagious pathogen in
| |
| − | Atlanta, GA. The spread is over 60 days.<br>
| |
| − |
| |
| − | <p></p>
| |
| − |
| |
| − | <p>With the most recent Ebola Outbreak, over 28 thousand were infected by
| |
| − | the deadly pathogen and an estimated 11 thousand died. Meanwhile, a
| |
| − | potent anti-Ebola antibody cocktail, ZMapp, was going through preclinical
| |
| − | studies. In a study where 18 heavily Ebola infected monkeys treated with
| |
| − | ZMapp, all 18 survived, including several in the hemorrhaging stage of
| |
| − | the disease. Given the timing and urgent need, ZMapp was approved for use
| |
| − | in humans. One of the first patients treated was Dr. Kent Brantly, the
| |
| − | American missionary worker who went on to recover from the disease.</p>
| |
| − |
| |
| − | <p>Antibodies are unique and powerful tools for eliminating pathogens.
| |
| − | They do so by both neutralization—the hindrance of function by surface
| |
| − | binding—and complementation—calling in the immune system. Unfortunately,
| |
| − | ZMapp’s utility was hindered by lack of supply, not an apparent inability
| |
| − | to neutralize the virus (as illustrated by the Rhesus model). Only 7
| |
| − | doses were available throughout the Ebola Outbreak, despite infection
| |
| − | rates in the thousands. Ultimately, it represents a problem, or complete
| |
| − | lack thereof, for rapid antibody production capabilities.</p>
| |
| − |
| |
| − | <p>A proposed solution was the tobacco plant. A relatively
| |
| − | well-understood and engineered organism, it was the method for making
| |
| − | ZMapp. Producers inject plant leaves with agrobacterium containing the
| |
| − | DNA for the therapeutic antibody. The plants grow and the antibody is
| |
| − | purified from the plant cell lysate. In theory, this is a quick and
| |
| − | inexpensive method for rapidly producing lots of antibody, dependent upon
| |
| − | arable land rather than high-sterility CHO-vats. In practice, it is
| |
| − | not.</p>
| |
| − | </div>
| |
| − | </div>
| |
| − |
| |
| − | <div class="minimal-dropdown__container">
| |
| − | <div class="minimal-dropdown__header">
| |
| − | <h2 class="minimal-dropdown__title">Some Solutions</h2>
| |
| − | <a class='minimal-dropdown__arrow'></a>
| |
| − | </div>
| |
| − | <div class="minimal-dropdown__content hidden">
| |
| − | <p>It might one day be possible to make drugs entirely without cells.
| |
| − | Protein-producing gels or other systems could produce drugs economically
| |
| − | in vitro avoiding the inherent biological complexity and metabolic needs
| |
| − | of living organisms. [<a href=
| |
| − | "http://www.nature.com/nmat/journal/v8/n5/pdf/nmat2419.pdf" target=
| |
| − | "_blank">1,</a> <a href=
| |
| − | "http://www.sciencedirect.com/science/article/pii/S1389172314001509"
| |
| − | target="_blank">2</a>]</p>
| |
| − |
| |
| − | <p>It might, alternatively, be possible to inject the mRNA of a desired
| |
| − | antibody directly, thereby offloading the antibody production to the
| |
| − | patient rather than delivering a bolus of externally produced antibody.
| |
| − | Moderna, for example, has developed synthetic mRNA that codes for
| |
| − | polypeptides while avoiding immune-surveillance (and therefore
| |
| − | elimination). It’s currently unclear how this mRNA will be targeted to
| |
| − | delivery into B cells, and for how long the B cells will continue to
| |
| − | produce antibodies. This approach, offloading manufacturing of antibodies
| |
| − | to the patient, has been extensively researched in the context of AIDS.
| |
| − | [<a href="http://www.ncbi.nlm.nih.gov/pubmed/8864752" target=
| |
| − | "_blank">3</a>, <a href="http://www.mdpi.com/1999-4915/6/2/428/html"
| |
| − | target="_blank">4</a>, <a href=
| |
| − | "http://www.nature.com/ni/journal/v14/n1/full/ni.2480.html" target=
| |
| − | "_blank">5</a>]</p>
| |
| − |
| |
| − | <p>In might be possible to design synthetic bacteria (like Synlogic) for
| |
| − | the gut that produce Nanobodies (small enough to be produced in bacteria
| |
| − | and lacking complex do-sulfide bonds). These pathogen targeting
| |
| − | nanobodies might prove capable of reaching the circulatory system after
| |
| − | being turned on by an exogenous transcription factor, however, these
| |
| − | nanobodies might still face the complication of improper glycosylation
| |
| − | and immune clearance. [<a href=
| |
| − | "http://europepmc.org/abstract/med/19876789" target="_blank">6</a>]</p>
| |
| − |
| |
| − | <p>Despite the volume of researchers working on futuristic solutions,
| |
| − | recombinant antibodies are known to work. They are less theoretical and
| |
| − | more a problem of logistics. And logistically, antibodies from Chinese
| |
| − | hamster ovary cells or tobacco plants never materialized during the 2014
| |
| − | Ebola Outbreak. So the question becomes: can microalgae produce properly
| |
| − | folded antibodies at a high enough concentration and at a cheap enough
| |
| − | cost to warrant their use as a widescale antibody production platform? We
| |
| − | believe it’s worth further investigation and will present the possible
| |
| − | long-term implementation of microalgae production facilities.</p>
| |
| − | </div>
| |
| − | </div>
| |
| − |
| |
| − | <div class="minimal-dropdown__container">
| |
| − | <div class="minimal-dropdown__header">
| |
| − | <h2 class="minimal-dropdown__title">A Green Safety Net</h2>
| |
| − | <a class='minimal-dropdown__arrow'></a>
| |
| − | </div>
| |
| − | <div class="minimal-dropdown__content hidden">
| |
| − | <p>Within each of us (health and medication depending) is an adaptive
| |
| − | immune system. A major cell in this system is the B Cell. Immunocompetent
| |
| − | B cells are covered in B cell receptors (BCRs). These BCRs respond to
| |
| − | non-self antigens. When a foreign antigen binds to a BCR, it activates
| |
| − | the B cell to turn into plasma B cells, dedicated producers of specific
| |
| − | antibodies against a portion of the antigen that triggered the
| |
| − | response.</p>
| |
| − |
| |
| − | <p>Some of the plasma B cells enter secondary lymphoid organs, otherwise
| |
| − | known as “germinal centers.” Here, B cells undergo rapid mutation so that
| |
| − | the selected-for plasma B cell population produces higher affinity
| |
| − | antibodies. The resulting plasma B cells begin leave the germinal center
| |
| − | to pump out high levels of antibody into the bloodstream. [<a href=
| |
| − | "https://www.rndsystems.com/research-area/b-cells" target=
| |
| − | "_blank">7]</a></p>
| |
| − |
| |
| − | <p>This is what the human species lacks on a macro-level infrastructure.
| |
| − | Hospitals and care-centers act as an innate response, responding in the
| |
| − | emergence of a contagion to quarantine the sick and provide nourishment.
| |
| − | They are not designed with the capability to rapidly adapt and attack the
| |
| − | pathogen. For good reason, drugs for human treatment undergo rigorous FDA
| |
| − | review before approval. The average inception to market timeline for an
| |
| − | FDA approved drug is 12 years (note: this is after the drug has been
| |
| − | developed). This is too long for rapid drug turnaround and represents a
| |
| − | significant threat to human health.</p><img id="outbreakgif" src=
| |
| − | "https://static.igem.org/mediawiki/2015/6/61/Algae_distribution_map-01.jpg"
| |
| − | style="width:100%">
| |
| − |
| |
| − | <p id="outbreakgifdesc"></p>A hypothetical map of distributed
| |
| − | algae-antibody production facilities. Orange dots are locations of
| |
| − | existing facilities that could be repurposed. Yellow dots are
| |
| − | hypothetical potential power plant algae hybrid facilities. They are
| |
| − | smaller in scale but repurposable in a time of need. Green dots are
| |
| − | potential large sized facilities. These too could produce commodity
| |
| − | goods, like food for livestock or subsidized biofuel, until needed
| |
| − | antibody.<br>
| |
| − |
| |
| − | <p></p>
| |
| − |
| |
| − | <p>In industrialized countries with significant carbon taxes, like the UK
| |
| − | and Australia, microalgae facilities might become commonplace alongside
| |
| − | power plants. Sapphire Energy, Sunomix, and Solazyme have demonstrated
| |
| − | the market potential of microalgae products. It would be strategic to
| |
| − | further distribute algae plants near heavily populated areas. Were a
| |
| − | pandemic to occur, these facilities could expunge their
| |
| − | commodity-producing microalgae and replace it with a high antibody
| |
| − | producing strain of microalgae, like recombinant <i>Chlamydomonas
| |
| − | reinhardtii</i> or <i>Phaeodactylum tricornutum</i>.</p>
| |
| − | </div>
| |
| − | </div>
| |
| − |
| |
| − | <div class="minimal-dropdown__container">
| |
| − | <div class="minimal-dropdown__header">
| |
| − | <h2 class="minimal-dropdown__title">Cost/Benefit</h2>
| |
| − | <a class='minimal-dropdown__arrow'></a>
| |
| − | </div>
| |
| − | <div class="minimal-dropdown__content hidden">
| |
| − | <p>The true benefit of using microalgae for antibody production is the
| |
| − | lower fixed cost of facilities.</p><img id="outbreakgif" src=
| |
| − | "https://static.igem.org/mediawiki/2015/8/89/Volume_Relative_Algae_Facility.jpg"
| |
| − | style="width:80%">
| |
| − |
| |
| − | <p></p><br>
| |
| − |
| |
| − | <p></p>
| |
| − |
| |
| − | <p>CHO facilities, on average, cost around $200M for 80,000L. A similarly
| |
| − | sized algae facility at 15,000L would cost an estimated $1.3M. With
| |
| − | economies of scale, algae production facilities become significantly
| |
| − | cheaper. $1B would be a 14 Billion Liter algae farm (5,500 acres)
| |
| − | according to one techno-economic analysis (Rogers, 2013. Algae
| |
| − | Research).</p><img src=
| |
| − | "https://static.igem.org/mediawiki/2015/b/b1/Producitivty_algae_graph.png"
| |
| − | style="width:80%">
| |
| − |
| |
| − | <p>The biggest challenge for microalgae will be improved productivity.
| |
| − | Because of fixed and variable costs, microaglae will not need to be 100%
| |
| − | as productive as CHO's (extremely unlikely in the near-term, given the
| |
| − | amount of research and time invested in CHO's), however, they will need
| |
| − | to improve 1-2 magnitudes over current levels. CHOs are far and beyond
| |
| − | the most efficient antibody producers, with some strains now exceeding
| |
| − | grams of product per liter of culture media. Furthermore, they are
| |
| − | entrenched in the industry: 61 of the 90 therapeutic proteins produced in
| |
| − | mammalian cells come from CHO's (Rader, 2015. Bioprocessing Journal).
| |
| − | Furthermore, of the 174 recombinant FDA approved drugs on the market,
| |
| − | only one is made by plant cells (Elelyso from carrot cell
| |
| − | culture).</p><img src=
| |
| − | "https://static.igem.org/mediawiki/2015/5/5d/Max_density_algae.png" style=
| |
| − | "width:80%">
| |
| − |
| |
| − | <p>An encouraging number is maximum biomass. Microalgae can quickly reach
| |
| − | high densities, with some culture conditions allowing biomass in excess
| |
| − | of 10g/L. With a higher cellular density, and significantly larger scales
| |
| − | for the same investment, microalgae may soon contend with CHO's.</p>
| |
| − | </div>
| |
| − | </div>
| |
| − |
| |
| − | <p>Sources: <a href=
| |
| − | "https://static.igem.org/mediawiki/2015/4/46/Screen_Shot_2015-09-10_at_7.44.36_PM.png"
| |
| − | target="_blank">Facility Volume vs Cost</a>, <a href=
| |
| − | "https://static.igem.org/mediawiki/2015/9/96/Screen_Shot_2015-09-10_at_7.44.56_PM.png"
| |
| − | target="_blank">Productivity</a>, and <a href=
| |
| − | "https://static.igem.org/mediawiki/2015/e/e1/Screen_Shot_2015-09-10_at_7.45.03_PM.png"
| |
| − | target="_blank">Cell Density</a></p>
| |
| − | </div>
| |
| − | </div>
| |
| − | </div>
| |
| − | </body>
| |
| − | </html>
| |