2019 Week 47: Reverse Engineering Paracetamol

Short version: A quick guide on reverse engineering a drug, no correlation between shoe size and penile length, and an infographic on the pension fund that owns 1% of the world.

Long version:

Reverse Engineering

Last week I wrote about patents. I cut out an incomplete section about the role of patents in drugs, where the costs of development (particularly testing for regulatory approval) can exceed a billion US dollars. Here parents are important because modern chemistry allows relatively easy reverse engineering to occur (i.e. working backwards from the product to understand how to make it). As an example, I briefly describe how this could be done with paracetamol (a common painkiller and antipyretic). I’m writing relatively late this week but will hopefully return to this post to update it with diagrams to better explain the process.

1. Purification
Even for a drug taken in relatively high doses such a paracetamol, the actual pill ingested is not a pure substance, but contains several “filler” agents to help make the pill more stable, easier to swallow, and to better control the release of the drug. Just as a black pen can be separated into its constituent dyes by water running through paper (e.g. ink smearing), so too can many chemicals under the right conditions be isolated by solvents flowing across a solid material. This is known as chromatography and is the underlying technique by which more advanced lab equipment such as HPLC can be used to isolate the different chemicals that make up a single tablet. By first running a reference material containing common “fillers” like carbohydrates (e.g. lactose, starch), we can more easily identify the unknown substances to investigate in identifying the target drug.

2. Identification
Once we have our purified drug, powerful techniques such as nuclear magnetic resonance (NMR) can give us structural information about the arrangement of atoms in the drug. Other techniques such as mass spectrometry and ultraviolet–visible spectrophotometry can provide additional information, but for a relatively simple molecule like paracetamol, NMR gives plenty of information.

3. Retrosynthesis
Knowledge of chemical synthesis is required to intuit how to make a given structure, but in trying to emulate the incredibly complex molecules of nature, a vast array of theoretical tools have been developed. The synthetic steps are drawn here, and for a synthetic organic chemist familiar with the reactions, working backwards from the structure may not be trivial, but is quite logical.

4. Synthesis
Now we can go into the lab and make the drug, following the retrosynthetic steps from the starting materials.

Penile Length and Shoe Size

Since I changed my default search engine to google scholar it has led me to accidentally search the literature when what I’m looking for is more mundane. This week while attempting to search “UK shoe size conversion”, the first result for me on google scholar was “Can shoe size predict penile length?“, a paper where two London urologists determined there is no relationship between shoe size and penis size. I haven’t been particularly concerned with penis size since puberty (if you are concerned, this NHS page may help you), but would (if asked) have assumed that the size of all body parts are roughly correlated, apparently not.

Norwegian Wealth Fund

The Norwegian sovereign wealth fund is the largest in the world, with US$1 trillion in assets and about 1% of almost all companies in the world. This interactive map shows the incredible list of investments.

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Photos from the Week

2019 Week 46: Patents

Short version: Patents reward innovators but limit the impact of new technologies. Also “patents” are the answer to the question “Why did Samsung build the only outdoor ice rink in Texas in a small town.”

Long version:

What I learned reading and thinking about patents

Patents are a part of the law, which is an ever changing system. As governments create and change laws, and those laws are interpreted and tested in courts, we collectively decide how the rewards of science and technology are distributed.

There is very little that is certain or obvious about patents. Their existence is both an incentive and a barrier to innovation. They can both enrich and impoverish inventors. They can both be utterly invisible and hugely controversial.

Patent trolling was used in the US to extort businesses, which seems to have peaked around 2015, and has since declined.

Some patents provide useful and specific descriptions of technology, whilst others are deliberately broad and vague.

Biotechnology has struggled to fit into the existing patent infrastructure, particularly as the line blurs between what is an invented object and what is part of nature.

Patent Trolls: Why Samsung built an ice rink in Texas

This article from Harvard Business School outlines how patent trolling, the use of frivolous patent lawsuits by businesses uninterested in innovation, led Samsung to try and win favour with potential jurors in Marhsall, Texas by building an ice rink there. Samsung also set up high school scholarships in the town, but when a supreme court decision meant that the jurisdiction where the suit was filed needed to be in the state of incorporation, the branding on the ice and the scholarships dissipated. More recently a paper was published about patent trolls last year.

Samsung, seeking favour with potential jurors, awarded scholarships to high school students in Marshall, Texas.

Patent Examples

The race to patent the Human Genome

Craig Venter’s company raced public researchers to be the first to sequence the Human Genome. You can read the story in Patrick Bradley’s paper. I found the twitter exchange below interesting, but was not able to verify or refute Venter’s claim that it was “untrue and was propaganda”. Certainly there was a race, and patents played a part, as they continue to do in biotechnology research.

BRCA1 and BRCA2

The other famous case within biotech patents is of Myriad Genetic’s patents on BRCA1 and BRCA2, two mutations related to breast cancer. Enforcing the patents meant diagnostic tests for inherited breast cancer were expensive. The debate centred on the question of whether DNA sequences could be considered a discovery or an invention, i.e. a technical question about how biotech fits within the existing patent system. Ultimately the patents were struck down. The underlying question, how much should we allow companies to profit from their research (at the expense of society, but to give incentives for more research) remains.

Intellectual Property and Piracy

Looking at patents led on to questions about copyright, trademarks, and intellectual property in general. In a world where replication of content is so trivial, and distribution technologies (i.e. the internet) are spreading so rapidly, it is unlikely legal enforcement can keep up in a meaningful way. This crash course provides some information, and I would like to return to think about the ethics of digital piracy, peer to peer sharing, and what the fairest way to regulate content could be.

A note about being connected on the internet

I find it strangely wonderful how connected the internet makes us. From a train, a coffee shop, or even my bed, I can reach out to authors and scientists, and access nearly all of the knowledge humanity has created. In researching this post, I could find out the Marshall high schools’ Samsung scholarship winners, or tweet at scientists like Craig Venter, or access patents from hundreds of years worth of inventions. It is such a powerful tool.

Other things in my life this week:

Rivers in Oxford have been rising, causing flooding around the Isis and Cherwell (see photos from the week). This excellent tracker from Anu Dudhia makes it easy to keep an eye on conditions.

I finished reading The Calculating Stars by Mary Robinette Kowal, it is excellent.

Three friends have signed up to the Edinburgh marathon, so running has gotten more social.

Photos from the Week – Flooding

2019 Week 45: Competition and Robots

Short version: Some thoughts on the blurry line where competition becomes toxic, and also robots.

Long version:

Competition

The story:
Athlete Mary Cain wrote and spoke with the New York Times about her experience training with the Nike Oregon Project, which ended recently after the head coach Alberto Salazar was banned due to involvement with doping. The environment at Nike Oregon Project was physically and mentally damaging for athletes like Cain, and for her the experience was clearly toxic. It is harder to say the project as a whole was toxic, because for other athletes (including Mo Farah) that environment led to enormous success. I am reminded of the ritual of stabbing a pin into ones chest practiced by elite military groups. Objectively this is painful and physically damaging, but so is much of what is used in selecting elite units.

My thoughts:
Pain, either physical or emotional, ought not always be avoided, but neither should it be sought out. In competitive environments an ability and willingness to suffer is a factor in success, whether the environment is a sports field, or a business sector, or a war. In my experience that suffering is much easier to bear when I feel I am choosing to face it, rather than it being imposed upon me. This is the contradiction of self-harm, that when suffering is imposed on someone they sometimes react by imposing further suffering upon themselves. It is worryingly unclear to me where the line is between good and healthy competition vs. a bad and damaging environment, but the evidence would suggest that the in a given environment like Nike Oregon Project, some can thrive while others will be crushed.

Robots

I encountered robotic arms that emulate a bartender in London this week, pictured below. It feels like something out of science fiction, where human like robots perform labour for their fleshy masters. While the spectacle of the arms at work is attention grabbing, a more elegant solution to dispensing beverages is the Coca Cola freestyle, (pictures of the internals from reddit here and here) which also can produce a large variety of mixtures, but in location and design is very similar to the more mundane soda dispenser. Consumer technology is often marketed through the cold lense of quantitative performance metrics, but our relationship with that technology (and our willingness to consume it) is just as emotional as the art that inspires it. We as a society built this robotic bartender (and so many other things), not because it was a practical solution to the problem of how to add tonic water to gin, but because it entertains us by feeling like the future we imagine.

Photos from the Week

2019 Week 44: Migrants

Short version: Thoughts prompted by recent news about migration. Some very brief notes on nutrition and technology news.

Long version:

Migrants

Content warning: if you’re having a bad day, maybe skip this one:

Context
Since it was revealed that the 39 people who died in a refrigerated lorry container were Vietnamese nationals attempting to illegally enter the UK, I’ve been thinking a lot about migrants. There are a number of things to unpack here, and I find it hard to tell if I am more hesitant because I lack expertise on the topic, or I find the exercise emotionally confronting.

Scale
I have written about how data can be unsympathetic. Just as mass shootings are powerful examples of a larger gun violence problem, so too are the 39 dead migrants a shocking but statistically small part of a much larger issue. The missing migrant program attempts to track data, and in 2016 there were 39 fatalities every two days for the entire year. These recent deaths make up a small fraction of the 2,589 total for 2019 so far.

Emotions
In some ways the idea of sneaking into the United Kingdom in a truck with 38 other people is utterly alien, and in other ways it is entirely relatable. The tension between those extremes creates some difficult emotions. I am a migrant, as are my siblings, my parents, most of my friends and colleagues. I know the desire to go to foreign lands to seek out opportunities, to live a more comfortable life, but only from a position of immense privilege where I take little risk in fulfilling those desires. Meanwhile I owe my existence to my parents who fled difficult times in the lands of their birth.


I found the following image most disturbing:

The last message from Pham Thi Tra My, 26, was sent to her family at 22:30 BST on Tuesday – two hours before the trailer arrived at the Purfleet terminal from Zeebrugge in Belgium.
Her family have shared texts she sent to her parents which, translated, read: “I am really, really sorry, Mum and Dad, my trip to a foreign land has failed.
“I am dying, I can’t breathe. I love you very much Mum and Dad. I am sorry, Mother.”

From BBC article Essex lorry deaths: Appeal to Vietnamese over victims’ identities

Pham Thi Tra had a smartphone, just like mine or yours. A piece of technology that could connect her with nearly any human on the planet. She could communicate with her parents half the world away from that refrigerated container, but could not call someone meters away to open it, to save her life and the lives of her fellow travellers. In a globally connected world she could trivially access so much information, and she decided the dangerous journey to the UK was worth the risk.

Justice
I am conflicted. Laws restricting migration that mean desperate people risk their lives to cross borders in such dangerous ways. These laws seem to exist to protect my quality of life and privilege at the expense of opportunities for others. I believe human beings should be of equal value be they born in Hanoi or Hobart, but the harsh economic reality is they are not. It seems unjust that laws exist to prevent them from pursuing the same quality of life, however if I were given the opportunity to open all borders around the world, I would hesitate. I do not know what such a world would look like, for example people might rush towards centers of wealth only to be crushed by competition with one another for those opportunities.

Some other unstructured thoughts about migrants:

Language:
The words we use around migration is not trivial. We tend to call wealthy migrants expats, (short for expatriate), compared to the derogatory connotations of “immigrant”. In Australia “asylum seekers” are often connected to “boat people“, perhaps in comparison to aeroplane people?

IOM Publications
Photos by Amanda Nero gave me some more insight into the camps around Calais. They also produce comprehensive reports.

Migrants Make Things Better
McKinsey and the UN conclude some significant positive effects of migration.

Australia
Australia has shockingly hypocritical views on immigration for a country overwhelmingly populated by non-native peoples. Some data on migration flows in Australia.

Scientific Advisory Committee on Nutrition (SACN)

I’m taking vitamin D supplements this winter, due largely to this pretty long report about vitamin D which feeds into the NHS recommendation. I would like to research and write in more detail about the authors and research behind such reports, but considering what is Changing My Mind, the authority of the government, academic, and health care institutions linked to the SACN reports is convincing.

Technology News

Science Fiction Settings:
Blade Runner was set in November 2019.

Asthma:
The NHS is thinking about the carbon cost of different inhalers.

Starcraft
AI is getting good at StarCraft II.

Google Buys Fitbit
The press release from Fitbit. Engadget article. DCRainmaker blog post. 2 billion dollars is a lot of money, but it is substantially less than the peak of Fitbit at nearly 10 Billion shortly after its IPO (see chart below). It doesn’t feel that long ago that Fitbit acquired Pebble, a maker of e-ink smart watches and a rarely successful kickstarter project.

Historic Market Cap of Fitbit

Photos from the Week