The Most Important Question You Can Ask: Then What?

The Most Important Question You Can Ask: Then What?


Life is full of next steps. In the academic literature, these things would be called “second order effects”. But, in real life, they’re called consequences (or unintended consequences). Each of our actions has an immediate effect and a range of different long term effects. For example, the short term effect of eating a McDonald’s hamburger may be enjoyment and satiety. However, the long term effect may be sleepiness and, eventually, weight gain (though, obviously, it takes more than one burger to get there).

The great art of life is in balancing the short term and the long term, so that one can have enjoyment with integrity - pleasure with purpose. But in most areas of life, we pay strict attention to the immediate consequences of things. We look at the immediate results of a social or economic policy and call it a victory (or a complete failure). We look in the mirror after each workout, hoping to see substantial changes in belly fat or physique. We play a game because it’s “so much fun”, and disregard the fact that it’s taking away from valuable study or work or social time. What is not present is always underrepresented, and opportunity cost is an invisible demon that steals us blind while we look right through him.

Luckily, there’s an antidote to this type of short-term thinking. It’s a simple question: “And then what?” Thomas Sowell, the great economist, once said that essence of economics is asking “and then what?”. The problem is that so few of us take the effort to do this very simple thing. It’s understandable, we get caught up in the moment, and we don’t particularly enjoy thinking in minute detail each and every moment of our lives. But in the coming era, it will become increasingly important for us to ask these kinds of things, as our interconnectedness makes ideas and new technologies spread faster than ever before.

If we think two or three steps ahead, it’s possible for us to make small changes in our products and services that can save us a lot of pain and heartache in the long run. Facebook would have been well served in asking this question when developing Beacon, the controversial program that shared a user’s purchases on other websites (like Blockbuster and Overstock) in Facebook’s social feed. Unfortunately, the system was opt-out instead of opt-in, and so many users found themselves with a sense of shock and betrayal as their personal shopping habits were shared far and wide in their social graphs. A ten minute exercise of “and then what?” could have easily prevented a mistake like this.

Of course, groupthink is a strong thing, and every single industry and organization falls prey to this fundamental human impulse. We’re tribal creatures, and we bind together at many different levels of life to feel a sense of belonging, and to get into positions that are advantageous to our desires and goals. But, an understanding of the complexity of the world, and second and third order effects, is essential for building technology - and dancing along with the chaos of life.

We technologists could really use a little reminder from time to time. And then what?

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This article was originally published by our sister site, Freethink.

For the first time, researchers appear to have effectively treated a genetic disorder by directly injecting a CRISPR therapy into patients' bloodstreams — overcoming one of the biggest hurdles to curing diseases with the gene editing technology.

The therapy appears to be astonishingly effective, editing nearly every cell in the liver to stop a disease-causing mutation.

The challenge: CRISPR gives us the ability to correct genetic mutations, and given that such mutations are responsible for more than 6,000 human diseases, the tech has the potential to dramatically improve human health.

One way to use CRISPR to treat diseases is to remove affected cells from a patient, edit out the mutation in the lab, and place the cells back in the body to replicate — that's how one team functionally cured people with the blood disorder sickle cell anemia, editing and then infusing bone marrow cells.

Bone marrow is a special case, though, and many mutations cause disease in organs that are harder to fix.

Another option is to insert the CRISPR system itself into the body so that it can make edits directly in the affected organs (that's only been attempted once, in an ongoing study in which people had a CRISPR therapy injected into their eyes to treat a rare vision disorder).

Injecting a CRISPR therapy right into the bloodstream has been a problem, though, because the therapy has to find the right cells to edit. An inherited mutation will be in the DNA of every cell of your body, but if it only causes disease in the liver, you don't want your therapy being used up in the pancreas or kidneys.

A new CRISPR therapy: Now, researchers from Intellia Therapeutics and Regeneron Pharmaceuticals have demonstrated for the first time that a CRISPR therapy delivered into the bloodstream can travel to desired tissues to make edits.

We can overcome one of the biggest challenges with applying CRISPR clinically.

—JENNIFER DOUDNA

"This is a major milestone for patients," Jennifer Doudna, co-developer of CRISPR, who wasn't involved in the trial, told NPR.

"While these are early data, they show us that we can overcome one of the biggest challenges with applying CRISPR clinically so far, which is being able to deliver it systemically and get it to the right place," she continued.

What they did: During a phase 1 clinical trial, Intellia researchers injected a CRISPR therapy dubbed NTLA-2001 into the bloodstreams of six people with a rare, potentially fatal genetic disorder called transthyretin amyloidosis.

The livers of people with transthyretin amyloidosis produce a destructive protein, and the CRISPR therapy was designed to target the gene that makes the protein and halt its production. After just one injection of NTLA-2001, the three patients given a higher dose saw their levels of the protein drop by 80% to 96%.

A better option: The CRISPR therapy produced only mild adverse effects and did lower the protein levels, but we don't know yet if the effect will be permanent. It'll also be a few months before we know if the therapy can alleviate the symptoms of transthyretin amyloidosis.

This is a wonderful day for the future of gene-editing as a medicine.

—FYODOR URNOV

If everything goes as hoped, though, NTLA-2001 could one day offer a better treatment option for transthyretin amyloidosis than a currently approved medication, patisiran, which only reduces toxic protein levels by 81% and must be injected regularly.

Looking ahead: Even more exciting than NTLA-2001's potential impact on transthyretin amyloidosis, though, is the knowledge that we may be able to use CRISPR injections to treat other genetic disorders that are difficult to target directly, such as heart or brain diseases.

"This is a wonderful day for the future of gene-editing as a medicine," Fyodor Urnov, a UC Berkeley professor of genetics, who wasn't involved in the trial, told NPR. "We as a species are watching this remarkable new show called: our gene-edited future."

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