Developing affordable, gene-based cures for sickle cell and HIV
futurehuman.medium.com
futurehuman.medium.com
- Accurate and precise CRISPR-based, human non-germline in vivo cell editing at scale still has some ways to go. We are not at the stage (yet) where a couple injections will be able to completely rewrite your genome. Accuracy and precision has room for improvement. In vivo needs more research (the ethics concerns and controversies is a huge barrier for this). And finally scale, which I will address below.
- A quick explanation of germline vs non-germline gene editing.
Non-germline: change just the genes in the affected area. Germline: change the genes in the sex cells (or their product, the zygote) so that the change will be perpetuated. The Stanford professor's controversial editing of the Chinese twins was germline based. Non-germline is hard because you have many many cells and right now CRISPR is still not perfectly precise. Delivering CRISPR to every part of the organ/afflicted area is still not yet well understood.
There was an article on HN a couple days ago on this. It was sensationalised and exaggerated but the point made is largely correct:
https://news.ycombinator.com/item?id=25096386 https://news.ycombinator.com/item?id=25096982
- The technology that finally makes it to market may not be CRISPR at all. With the announcement two days ago by Deepmind, the field of proteomics, and by proxy biology, has been fundamentally changed. The impact to computational biology is akin to ImageNet overshadowing the Lisp/Prolog based expert systems, and their successors' decision trees. History has been written. The repercussions of that blog post is greater for humanity than the moon landing. You often see on HN people complaining how top minds and talent are now working on better ads systems and recognising cat photos instead of real hard tech. The cat photo recognition people just wrote their names in the biology textbooks of the future. Silicon valley loves anti-aging research. That Deep Mind blog post alone possibly added decades to our lifespan than any past effort by Aubrey De Grey et al. or the Methuselah Foundation. Biotech startups might actually be profitable now (hahaha)
I guess the external membrane does, and CRISPR thus needs to be present inside of the cells before they become infected? Is the delivery mechanism once again the limiting factor?
Sickle Cell protects against malaria, which is also a horrible disease. The Gates Foundation hopes to do something about Sickle Cell in the next ten years and hopes to eradicate malaria in the next twenty (see below). I hope they decide this needs to be more of a coordinated effort.
The Bill & Melinda Gates Foundation has committed nearly $2 billion to antimalaria efforts, and Bill Gates has said he believes the disease can be wiped out by 2040.
Malaria today is transmitted in ninety-five countries, accounting for nearly half of the world’s population. Eighty-nine percent of all reported cases are in sub-Saharan Africa
It's a remarkable breakthrough.
None of the currently approved drugs can modify the underlying pathology of the disease. Voxelotor, first of its kind, is an orally administered drug that can alter the underlying disease pathology (by increasing the affinity between Hb and oxygen) and inhibit sickling of red blood cells.
I knew being heterozygotic for sickle cell helped. Does having two copies of the gene have a net benefit? ... Wiki seems to say no: "The protective effect of sickle cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria." https://en.wikipedia.org/wiki/Sickle_cell_disease#Malaria_pr...
Maybe I am missing something and the plan here is to leave Sickle Cell trait alone and only subject people with Sickle Cell Disease to what amounts to genetic experimentation. I find that ethically questionable, but perhaps there are people who think that makes sense.
To me, fixing this means getting rid of the mutation. The mutation exists because it is protective. If you remove that protection without first removing the reason it exists, I find that also morally questionable. First, eradicate malaria from the region. Then eradicate the trait.
You could reduce incidence of the disease dramatically without coming up with Frankensteinian medical experiments by testing everyone for the trait as a condition of getting a marriage license and trying to get carriers to stop breeding with other carriers. It would be a social intervention, not a medical intervention, and it's completely humane.
Of course it wouldn't make headlines as being ooh, shiny new tech and some people would no doubt have a cow about it for some reason or other, like "What right do you have to tell me whom I can love?"
But as someone with a different homozygous recessive disorder (who also has a child with the same thing), that was more or less my policy after I was diagnosed and was getting a divorce. I didn't wish to risk getting pregnant by a carrier again, so I did what I could to protect myself against that scenario.
Throw in words like ethically questionable and some folks will probably hit the downvote button in knee jerk response to perceived "SJW" stuff without trying to understand the point of the comment.
I think you are missing some context. Most if not all gene therapies do not eliminate the heritable trait. In this case, The the gene therapy would alter the DNA causing the disease in the bone marrow, not the reproductive DNA in the testes or ovaries. It doesn't help that articles and speakers use sickle cell to refer to both the disease and gene.
To me, social controls on who can marry and who can breed with who are much less humane than offering experiential gene editing to sick and willing people. This would be followed by offering tested and proven gene editing to sick and willing people.
>that was my policy after I was diagnosed and was getting a divorce.
I think that is a reasonable and cost effective solution, but there are other options. For those with the means, embryonic screening is an option. In the future, it may be possible to remove all negative symptoms from the homozygous carrier.
There is also the topic of dominant genetic disorders like huntington's disease, which can not be prevented in children by screening partners. Without medical solutions, these people can not have children without risk. With genetic medical intervention, the carriers as well as their children can be spared from an awful degenerative disease.
Trying to be diplomatic about it ends up making me "look stupid." Trying to be confident about my views ends up making me look like a narcissistic and contemptuous asshole who thinks everyone else is stupid.
My mental framing for the space is different than yours. That doesn't, per se, mean I'm wrong or stupid.
My mental framing is rooted in having lived with a genetic disorder my entire life and having raised a child with the same disorder and getting diagnosed late in life.
The problem space for a dominant genetic disorder like Huntington's Disease is fundamentally different from that for a recessive disorder. Mental models for how to address them should be fundamentally different as well.
So telling me "That doesn't work for a dominant disorder" isn't really a valid rebuttal of anything I've said. I'm not suggesting it as policy for dominant disorders.
>Maybe I am missing something and the plan here is to leave Sickle Cell trait alone and only subject people with Sickle Cell Disease
To confirm, the plan here is to leave Sickle Cell trait alone and only subject people with Sickle Cell Disease to a change which will relieve their disease symptoms, but not change any heritability.
I thought I addressed both recessive and dominant disorders in my comment and I validated your mate selection strategy as a personal choice.
Where I disagree is (1) the idea that introducing a legal or social policy to address recessive disease is better than offering a medical solution and (2) that non-germline genetic modifications are morally questionable by their very nature.
If your personal experience having lived with a genetic trait leads you to a different conclusion on the above points, I would be interested in hearing why. If you were saying something different that I entirely missed, I would also be interested.
Social means to address serious conditions used to be the default norm for many things, such as STDs. Historically, if you turned up positive for an STD, a social worker asked you for the names and contact info of all recent sex partners, contacted them, let them know they had been exposed (or had possibly been the person who gave it to you) and offered them testing and treatment.
That focus on social stuff in medicine has changed in recent years, in part because we have so much medical technology that we default to expecting people to go to a doctor's office or a hospital for testing and treatment. It used to be the norm that a physician visited your home with their little black bag and treated you there. I think that probably stopped being the norm when medical tech advanced to the point where you couldn't fit it all in a little black bag, basically.
Doctors used to be the smartest and wisest people in a lot of communities. If they visited your home, they could get some idea of the real reason you were sick without asking you uncomfortable questions (like is the place a filthy pigsty).
In addition to historical medical practices being pertinent to my thinking here, a lot of this falls under a broad category of issues that I think of as "human sexual morality." It's something I've thought a lot about over the years for a long list of personal reasons and it's very much my own set of mental models, so that makes it hard to talk about with anyone else and I tend to mostly not bother.
As far as I can tell, "human sexual morality" is mostly about two things: 1. Trying to prevent economic disaster for both individuals and society and 2. Trying to prevent medical disaster for both individuals and society.
There is currently a global pandemic on and we are currently imposing all kinds of restrictions on human behavior for such prosaic activities as going shopping in order to prevent the spread of disease. So it's a bit aggravating to be hearing in this current climate that someone has some big objection to behavioral intervention as a means to prevent disease.
Some of what happened historically with regards to how we handle STDs and medicine generally in the US is that AIDS came along and in the US that was predominantly a disease infecting gay men and people using illegal IV drugs. Neither population wished to give up their contacts to social workers because they had a legitimate concern that it would be used to persecute gays and drug users.
So they advocated for medical treatments for AIDS and HIV rather than the standard social intervention of the day of asking for the names of all the people who might have given it to you. And this became something of a turning point in how we handle disease.
We increasingly look for a pill or surgery when we historically relied on things like monogamy, an expectation of virginity before marriage, shotgun weddings, social workers taking the names of your contacts, doctors visiting your home in person where they could casually see a lot of things about your life without asking that could inform their treatment decisions, etc etc.
Medicine has veered into a dangerous area where human bodies get treated like some kind of specimen in a petri dish and where far too many people seem gripped with this deluded idea that your lifestyle has nothing whatsoever to do with your health outcomes and we presume that any kind of "official" intervention in your lifestyle choices is some kind of communist plot rather than a standard historical means to control disease.
I wish we would focus on figuring out a better path forward, one that genuinely respects human rights more than our current default practices tend to do, while not obtusely acting like "health care" is solely about pills, vaccines and surgeries while diet, lifestyle and even social practices are off limits for trying to solve some of the problems we currently have.
The alternative wouldn't need to be social controls. A program of free genetic testing simultaneous with typical childhood vaccines might suffice, with only the family given the results. Armed with such knowledge well before they begin developing relationships, many if not most people might voluntarily employ a disassortative mating strategy independent of any sort of state coercion.
And that doesn't even need to be the alternative. It could just be the primary approach, with gene editing for handling the remaining and, hopefully, dramatically reduced case numbers.
In the Cystic Fibrosis community, many people have no idea they are carriers and know nothing about the condition until they have a child with the condition. And then they are left with the gut-wrenching decision-making process of "Should we have more kids, knowing there is a 25 percent chance they will also have this Dread Disease?"
This is a huge hot-button topic in the CF community, or was when I used to participate in CF discussion spaces. As the saying goes, most people "wouldn't wish this on their worst enemy," much less their own child whom they have to raise.
(If they have any idea what is involved, most people wouldn't wish raising such a child on themselves. It's a significant burden to care for such a child. That alone is enough reason for many people to not want a child with a serious genetic disorder.)
The capability to perform these tests already exists, but it would be necessary to make them cheap and available. For those with money, embryonic screening already exists for most monogenic and many polygenic traits, including IQ, height, ect.