Week 1 HW: Final Project Ideas

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Homework 1

(1) What you would like to biomanufacture and why?

I would metabolically engineer an organism to produce naloxone, the opioid overdose reversal drug. I have had a life long connection to harm reduction and protecting people who use drugs. Currently, amidst an opioid crisis and the recent memory of the Sackler OxyContin scandal, public supply of naloxone is largely due to “corporate goodwill” and utilization of opioid settlement dollars to fund Overdose Education and Naloxone Distribution (OEND) programming. But what will happen if public policy shifts away from harm reduction and back towards a more punitive model like the 1980s and 90s? When the pharmaceutical corporations feel they have repaid their “debt to society”? Prices of naloxone could skyrocket like other life-saving medications such as epinepherine and insulin. Creating a scalable system for production of naloxone in a simple living system could help keep costs low and give non-profit pharmaceutical companies or co-ops a competitive chance.

(2) What living system would you use?

Red algae seems interesting as it is an autotroph and could be kept alive with minimal inputs in a photobioreactor. Its sensitivity to shear may be useful in ease of extraction.

(3) How would you use automation?

I don’t see why almost the whole production couldn’t be automated. Sensors to control nutrients, pH, temperature, pressures, and flow rates of the system. Automated spectroscopy could determine when to extract naloxone from the system. The extraction process could be automated with liquid handlers and a preparative chromatography instrument.

(4) How much would you need to make, and how long would it take?

(a) How much?

The goal of naloxone distribution in harm reduction and public health circles is known as naloxone saturation. The idea is that anytime there is an overdose, there should be someone nearby with naloxone, able to reverse it. More research is still needed to determine exactly how much is needed including working with local health departments to determine coverage gaps. Presuming you want there to be some , anywhere as a standard part of a first aid kit and there have been Target: one year of US naloxone demand at saturation.

People with past-year OUD, US: 5,000,000
Kits per person per year: 2
Naloxone per kit (2 x 4 mg nasal): 8 mg

5e6 x 2 x 8 mg = 80 kg naloxone

Institutional stock (EMS, police, schools, libraries, hospitals, shelters), +75%:

80 kg x 1.75 = 140 kg -> round to 150 kg naloxone API / year

– (b) How long?

Claude really took the wind out of my sails on this one. In yeast at ~100 g/L dry cell weight and 2 mg/L product, specific content is about 20 µg per gram dry weight. Assume, charitably, you port that specific content into a red alga.

A well-run Porphyridium photobioreactor reaches maybe 3 g/L dry weight over a 10 to 14 day batch. Same 20 µg/g gives you about 60 µg/L per batch, roughly 36 batches per year if you never stall. Required volume: V = 30 kg / (60 µg/L × 36 batches/yr) = 3×10⁷ mg / 2.16 mg/L·yr ≈ 1.4×10⁷ L of working volume That’s 14,000 m³ of closed photobioreactor running continuously. The largest closed tubular PBR installations in the world are two to three orders of magnitude smaller. If you built a generous 100 m³ facility, which would already be among the bigger closed systems anywhere, you’d need about 140 years to accumulate one year of US naloxone supply5.

5. What don’t you know yet?

There’s so much I don’t know, but I’d say the biggest bottlenecks would be figuring out what enzymes could achieve the synthesis of naloxone in vivo. Naloxone is synthesized from oxymorphone with synthetic reagents such as Grignard and Burgess reagent1. Enzymatic equivalents or alternative routes would need to be explored to convert the teriary amine from a methyl to an allyl. How to insert synthetic sequences into algae would be the next step, they aren’t quite as well studied as other models2.

References

  1. Endoma-Arias, M.A.A., Cox, D.P. and Hudlicky, T. (2013), General Method of Synthesis for Naloxone, Naltrexone, Nalbuphone, and Nalbuphine by the Reaction of Grignard Reagents with an Oxazolidine Derived from Oxymorphone. Adv. Synth. Catal., 355: 1869-1873. https://doi.org/10.1002/adsc.201300284
  2. Arad SM, Levy-Ontman O. Red microalgal cell-wall polysaccharides: biotechnological aspects. Curr Opin Biotechnol. 2010 Jun;21(3):358-64. [doi: 10.1016/j.copbio.2010.02.008](doi: 10.1016/j.copbio.2010.02.008). Epub 2010 Mar 10. PMID: 20219344.
  3. Sugarman OK, Hulsey EG, Heller D. Achieving the Potential of Naloxone Saturation by Measuring Distribution. JAMA Health Forum. 2023;4(10):e233338. doi:10.1001/jamahealthforum.2023.3338
  4. “Use naloxone distribution data…” prompt. Claude, Opus 5 version, Anthropic, 22 Sept. 2026, claude.ai/chat.
  5. “Calculate how much naloxone would be needed for saturation in the US in a year” prompt. Claude, Opus 5 version, Anthropic, 22 Sept. 2026, claude.ai/chat.