[colechristensen]

Also it's a multi-species mutation that stuck in humans and the great apes which broke the urate oxidase enzyme.

If we fixed it, nobody would get gout.

I kinda wonder sometimes why medicine doesn't try to fix some of these species level genetic problems more broadly or more quickly. There's this enzyme every other mammal produces, why isn't there a fast track to engineering a micro-organ to produce it or inject an engineered version in gout patients (I did some research and yes people are somewhat doing these things... slowly)

Why can't I, a healthy adult, be genetically engineered to start producing my own Vitamin C like every other mammal?

[FL33TW00D]

The paternalistic state does not allow you autonomy over your own body.

e.g the amount of backlash thought emporium got when he genetically engineered himself to remove lactose intolerance: https://www.youtube.com/watch?v=J3FcbFqSoQY

Risky, but it's his body!

[striking]

It's a cool video but it's formatted almost like a tutorial, with folks in the comments appearing excited to actually try it on their own bodies with lab equipment they have access to. It's pretty irresponsible given that I don't think he fully expressed the risks of doing this to your own body.

[dekhn]

It's not just risky, it's hard to know if it really "worked" for many reasons. This is why we run double-blind, randomized control trials- to be convinced that the treatment "worked".

[FL33TW00D]

He went from being unable to eat many foods, to eating a full cheese pizza on camera. Pretty sure it worked.

[lukas099]

Whom did he get backlash from and what was their stated reason?

[rjdj377dhabsn]

That's incredible. How has he not patented the process and made a fortune from selling a cure for lactose intolerance?

[tomrod]

> The paternalistic state does not allow you autonomy over your own body.

Evidence to the contrary - fishing during free time.

[MSFT_Edging]

I would love for my gout to be genetically engineered away.

I didn't have a flare up until my late 20s but it finally explained the very slight ache in my big toe. After the first one, the second and third happened within a year. I stopped drinking almost entirely aside from some gin a few times a year.

I reduced various food consumption with no change. Whisky/beer will cripple me if I have more than one of either. After some research, vegan marathon runners are even plagued by this.

[monkpit]

I second Allopurinol. Your doctor will try to tell you gout is due to your diet and lifestyle. The reality is (according to nearly everyone who actually has gout on the internet) that you just _have gout_ - you can’t diet it away.

I cut out all drinking and went vegetarian after a gout diagnosis and still had flare ups. I never drink sugary drinks or eat fast food, and yet doctors would constantly recommend cutting these out and “lifestyle changes”.

Allopurinol is the only thing keeping me from being bedridden on days I can feel a flare up.

[morkalork]

If you haven't already tried it, Allopurinol is an effective and almost entirely side-effect free treatment.

I lament the time I lost living without it!

[nradov]

For anyone who wants a deep dive on uric acid metabolism this Peter Attia Drive podcast with Rick Johnson, M.D. is a great resource.

https://peterattiamd.com/rickjohnson2/

[TallGuyShort]

When choosing what my life's work would be, I filtered out tasks that involved genetically engineering humans so that my solution cold compete with "eating a nice, fresh orange". Maybe I'm just lazy and unambitious.

[rsync]

Evolution isn’t stupid … it’s not a random outcome that we don’t produce our own vitamin c, or have an appendix, or (urate oxidize blah blah).

I wish you all the luck in fixing these problems and would be fascinated to see the outcomes… However, this notion that these changes would be cost free is a mistaken one.

Mutants with these characteristics have certainly existed over evolutionary time… Our version outcompeted them.

[colechristensen]

>Evolution isn’t stupid

Evolution also isn't smart. Have so much of something in your diet and you'll tend to lose the ability to manufacture it because there's little evolutionary pressure to maintain it. If you're a VitaminCless mutant you don't die and your children survive just fine and suddenly this becomes common in the species.

It didn't get lost because it was advantageous for it to be gone, it just wasn't important enough to get maintained.

[stubish]

Evolution does not optimize for quality of life. And evolution certainly creates some pretty stupid outcomes, as it favors slapping on quick fixes at random rather than intelligently engineering the problem away. So we have hardware problems like our blind spots that got 'fixed' in software, unlike other species that evolved eyes separately and happened to get the wiring right.

[devmor]

WRT genetic engineering, I believe the main barrier to these things is that our genes are quite multipurpose. You may turn on the ability to produce vitamin C, and that same sequence of genes could also turn your eyeballs into calcified lumps.

[colechristensen]

Eh, while that's true for many things, there are plenty of genetic diseases for which it is not ("diseases" or whatever you might call the human lack of vitamin C synthesis)

In this case the gene encoding L-gulonolactone_oxidase is broken, and that's the last step in the process. That gene catalyzes something into a substance which decays into vitamin C.

[roywiggins]

First you need a gene therapy delivery system that doesn't produce any off-target mutations at all, ever.

[colechristensen]

Extract tissue from patient, build a cell line, CRISPR in vitro, build a cell line, sequence to verify. Use verified cell line to build pseudo-organs or to inject cells or stem cells.

ex vivo gene therapy.

[roywiggins]

Cells don't survive sequencing, any that you do implant have not been sequenced. At best you can get some confidence that the error rate is small.

[colechristensen]

This is why I said build a cell _line_, i.e. cells that all come from a single parent cell. Clones. Make monoclonal stem cell lines, use CRISPR on them, make a NEW monoclonal cell line post-CRISPR and pull some cells to validate success or failure.

[roywiggins]

Whatever engineered solution could happen, it will almost certainly have more side effects than a diet that includes vitamin C, and even if not, cost way more.

[jyounker]

> I kinda wonder sometimes why medicine doesn't try to fix some of these species level genetic problems more broadly or more quickly

Because the technology to do so doesn't exist yet.

We're at the point where we're trying to fix only most severe conditions, conditions for which there are no other treatment options.

[mapt]

Gemini:

> Therapeutically, recombinant urate oxidase (like rasburicase or pegylated urate oxidase) is used as a medication to rapidly lower uric acid levels, treating tumor lysis syndrome, hyperuricemia, and gout, especially when other treatments fail or are contraindicated.

Wikipedia:

> It has been proposed that the loss of urate oxidase gene expression has been advantageous to hominoids, since uric acid is a powerful antioxidant and scavenger of singlet oxygen and radicals. Its presence provides the body with protection from oxidative damage, thus prolonging life and decreasing age-specific cancer rates.[15]

> Children with non-Hodgkin's lymphoma (NHL), specifically with Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (B-ALL), often experience tumor lysis syndrome (TLS), which occurs when breakdown of tumor cells by chemotherapy releases uric acid and cause the formation of uric acid crystals in the renal tubules and collecting ducts. This can lead to kidney failure and even death. Studies suggest that patients at a high risk of developing TLS may benefit from the administration of urate oxidase.[17] However, humans lack the subsequent enzyme HIU hydroxylase in the pathway to degrade uric acid to allantoin, so long-term urate oxidase therapy could potentially have harmful effects because of toxic effects of HIU.[18]

> Higher uric acid levels have also been associated with epilepsy. However, it was found in mouse models that disrupting urate oxidase actually decreases brain excitability and susceptibility to seizures.[19]

> Graft-versus-host disease (GVHD) is often a side effect of allogeneic hematopoietic stem cell transplantation (HSCT), driven by donor T cells destroying host tissue. Uric acid has been shown to increase T cell response, so clinical trials have shown that urate oxidase can be administered to decrease uric acid levels in the patient and subsequently decrease the likelihood of GVHD.[20]

> Urate oxidase is formulated as a protein drug (rasburicase) for the treatment of acute hyperuricemia in patients receiving chemotherapy. A PEGylated form of urate oxidase, pegloticase, was FDA approved in 2010 for the treatment of chronic gout in adult patients refractory to "conventional therapy".[21]

As a general rule though, you can effectively treat/prevent gout by significantly increasing consumption of water and by replacing proteins with cereal grains (or fruits and vegetables or vegetable fats). These are inexpensive, fairly safe solutions.