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Can Graphite Bio Realize the Promise of CRISPR Gene Editing to Develop One-time Cures?

Graphite Bio is pioneering a precision gene editing approach that has the potential to transform health by achieving one of medicine’s most elusive goals:…

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Josh Lehrer, MD, MPhil, FACC, is
CEO at Graphite Bio.

One dose, one cure. Countless researchers with this dream have worked for decades toward developing life-saving medicines for genetic diseases. That’s gene therapy’s goal: to fix DNA errors and see a pathological condition halted or reversed with just a single shot.

Graphite Bio is pioneering a precision gene editing approach that has the potential to transform health by achieving one of medicine’s most elusive goals: to precisely “find & replace” any gene in the genome. Graphite Bio’s UltraHDR gene editing platform takes CRISPR beyond cutting and harnesses the power of high-efficiency precision DNA repair.

Using an adeno-associated virus called AAV6 as a delivery vehicle, Graphite Bio uses a DNA template to correct genetic mutations, replacing entire defective genes with functional genes or inserting new genes into predetermined, safe locations in stem cells. The company was co-founded by academic pioneers in gene editing and gene therapy, including Maria Grazia Roncarolo, MD, and Matthew Porteus, MD, PhD.

Graphite Bio’s platform is being used to develop genetic medicines targeting several blood diseases. Nula-cel, formerly GPH101, is Graphite Bio’s lead investigational therapy that will be evaluated as a potential cure for sickle cell disease (SCD) patients. Nula-cel uses the UltraHDR platform to directly correct the point mutation in the beta-globin gene that causes SCD, changing sickle hemoglobin (HbS) to normal adult hemoglobin (HbA).

Graphite Bio claims to be one of the first companies advancing a genetic therapy with the potential to change a disease-causing gene back to normal for any indication. The multi-center, open-label clinical study called CEDAR is designed to evaluate the safety, preliminary efficacy, and pharmacodynamics of GPH101 in adult and adolescent patients with severe SCD. In August 2022, Graphite Bio dosed the first patient in the CEDAR trial, with initial proof-of-concept data from the Phase I/II CEDAR trial anticipated in mid-2023.

Graphite also has a research program for treating beta-thalassemia, one of the most common autosomal recessive disorders. This genetic blood disorder is characterized by reduced production of beta-globin, a protein that forms oxygen-carrying hemoglobin with alpha-globin. Graphite seeks to replace the mutated beta-globin gene with a functional gene and restore adult hemoglobin (HbA) expression. In addition, Graphite has an early-stage research program for treating alpha-1 antitrypsin (AAT) deficiency, a severe inherited genetic disorder that can cause progressive lung and liver disease. The program leverages the company’s targeted gene insertion approach to increase AAT protein production permanently.

GEN Edge talked through Graphite Bio’s underlying strategy to develop several genetic cures with CEO Josh Lehrer, MD, MPhil, FACC.

GEN Edge: Josh, how did you end up joining Graphite Bio?

Lehrer: Before joining Graphite Bio, I was the chief medical officer at Global Blood Therapeutics (GBT) and worked for many years on developing Oxbryta, the first approved mechanism-based therapy for sickle cell disease (SCD). We had our co-founder, Matthew Porteus, come to give a seminar at GBT to talk about his groundbreaking work. When I heard what he was doing, I was floored. He had figured out how to make a decades-long dream in the field of genome engineering a reality. He showed us edited cells from a patient with SCD that had been corrected, indistinguishable from the cells of a patient’s unaffected siblings or parents. This was simply incredible. I saw an amazing opportunity to take what I had learned and join with Matt to both build a company around this platform and also rapidly move into the clinic to hopefully transform the lives of people living with SCD.

We started the company at the beginning of the COVID-19 pandemic, in April 2020, and have grown to over 100 employees. We became a public company just over a year ago and are fortunate to have the resources we need to advance our sickle-cell program and, in parallel, several other genetic therapies.

We’ve also thought about not just the technology, the platform, and the cell engineering, but how we can get these genetic therapies to be more than a headline, more than an exciting publication, more than a handful of patients treated to really impact large numbers of people in need. We realized that the conditioning treatment—how a patient’s bone marrow is treated to make room for the gene-edited stem cell therapies—is as critical as the editing technology. We have used our experience in stem cell biology and immunology to begin research on a new approach to conditioning. We are now developing what we hope will become a best-in-class, non-toxic antibody targeting approach, ultimately enabling a one-time cure that wouldn’t require a hospital stay or have chemotherapeutic conditioning risk—a very different paradigm than what we can currently offer patients.

GEN Edge: What is Graphite’s strategy to move these therapies quickly through approval?

Lehrer: Since our founding, our focus has been on advancing our programs with a sense of urgency, and ultimately getting our potentially curative therapies to as many patients as possible.

We are planning to move quickly through our clinical trials, leveraging the experience of other clinical trials in SCD. But we are also thinking about this end-to-end. We’re trying to think of what success means with a long-term view—not just how we get this technology to the initial clinical data readout, but how we generate data to demonstrate the unique advantages of a definitive gene correction approach. This means designing our clinical trials with new endpoints that can measure the benefit of a complete cure versus an indirect approach, and these endpoints could ultimately translate into an approval for a greater number of patients with sickle cell disease.

We are also thinking holistically, beyond our clinical trials for Nula-cel, about the barriers we need to overcome to impact more patients. If the science tells us we should be developing a new antibody to improve conditioning and remove a barrier to access, then it makes sense to do that, even if that wasn’t part of our initial focus or strategy. This also means investing early in advancing how we manufacture our therapies, making the process more scalable and reducing costs. We should invest in these strategic priorities to ensure that our programs have the most extensive potential patient benefit. They may be much more important than adding a third or fourth program to our pipeline.

GEN Edge: Does Graphite Bio consider partnerships to expand the platform’s reach?

Lehrer: We think about partnerships if others can bring unique expertise or resources that help us leverage our gene editing platform in additional directions. We are starting to turn to those conversations a little more, where we think we have the best tools for efficiently integrating DNA in virtually any cell type ex vivo. And that is applicable outside of hematopoietic stem cells—to engineering T cells, NK cells, iPS cells, or other types of cells that could be therapies in other areas. For example, we’re probably not going to identify new cancer targets ourselves. These would be perfect opportunities to collaborate with other companies, where we can do the editing more efficiently and other companies can provide biological or developmental expertise in different therapeutic areas.

GEN Edge: What drove the decision for Graphite Bio to become a public company?

Lehrer: We wanted to leverage a platform broadly and have the opportunity to broadly consider what’s required to cure SCD patients, beyond just one clinical trial and one data readout. If we were focused on creating value as a private company, we’d stay private a company, get the first few patients of data in our SCD program, increase value, and then figure out what’s next. We would be moving forward in serial.

But we needed more resources and a bigger team because we have bigger ambitions. For example, in SCD or any cell therapy, you must think about the commercial manufacturing process from the beginning. If not, you end up with what we’ve seen happen with other companies—making many changes along the way and getting delayed for years. That requires a significant upfront investment, a big team, and a public company’s resources. We were fortunate that the market was very receptive when we decided to go public.

GEN Edge: What milestones has Graphite Bio set for the next five years?

Lehrer: If we’re having this conversation in five years, bringing this technology to people living with SCD and realizing its full potential is a big part of what’s driving us. We are moving that forward, validating the platform, showing that clinically we are different, and then translating that into endpoints demonstrating that we can impact all aspects of the disease and treat all severely affected patients who need a cure. We want to go beyond what others have shown, which is a reduction in pain, to show that our approach can be a definitive cure by producing normal red blood cells, preventing strokes in kids, preventing organ damage, and essentially phenocopying what is the gold standard for cure inSCD: allogeneic transplants.

In five years, if we have a best-in-class antibody conditioning therapy that can be administered in the outpatient setting to create room in the bone marrow niche for engraftment of our stem cell-based cure, then we can bring this therapy to kids with SCD who aren’t yet experiencing complications and stop the disease before the damage begins. That would transform how we think about SCD—every child born with the disease could have a chance to live a completely normal life. And we’re thinking about manufacturing cell therapies as an engineering problem to where we can get costs down from where they are now to make this accessible broadly and see a significant impact from a public health standpoint.

We’d hope to take the same approach to other severe genetic diseases. We have a program in beta-thalassemia that would synergize with our approach in SCD. It was even more technically challenging because we need to use our gene editing technology to replace an entire gene.

Our gene editing technology can also precisely insert genes into stem cells to give them new functions, potentially bringing one-time cures to many other types of genetic diseases using our platform. These cells can repopulate brain microglia within the central nervous system (CNS) and permanently deliver proteins across the blood-brain barrier to fight neurodegenerative diseases, for example. We could also engineer stem cells to produce red cell precursors as protein factories to make enzymes and proteins to treat diseases like alpha 1 anti-trypsin deficiency or to produce clotting factors for hemophilia. Having some of these programs in the clinic to show the broader potential of our platform is something else we’d like to see in a five-year timeframe.

Beyond that, we’re starting discussions about how to leverage our platform outside of hematopoietic stem cells. We want to pursue new programs where we think we can solve a different need or have a differentiated therapy. An example would be if there’s a strong hypothesis around a better CAR T that requires multiplex editing, or insertion of several different transgenes. We have a highly efficient way of doing this, and this could be a productive collaboration with a company that brings cancer biology expertise.

GEN Edge: What are the rate-limiting factors to getting Graphite Bio to these milestones?

Lehrer: The rate-limiting factor in demonstrating clinical data and clinical translation with these therapies is manufacturing—the CMC (chemistry, manufacturing, and controls). I’ve previously worked in small molecules and biologics; the difference here with gene editing is that there’s no target risk. If you can do what you’re trying to do, you can cure a patient because you’re changing a dysfunctional gene back to a functional one. You can also get to proof of concept in the lab or even animal models. A postdoc project can lead to a development candidate. So, that part is fast, and that’s exciting.

But where things can be slower, because the steps are not as efficient and the standards are still evolving, is going from that to the clinical material and then commercial supply. This requires strict controls and analytics. And this is a new field, so to some extent, the testing required by the FDA is a moving target. Regarding manufacturing, there’s a lot of experimentation, continued investigation, and learning that has to happen in tandem with your clinical experience. That isn’t true if you make an antibody or a small molecule.

Initially, we’re using a GMP facility built at Stanford, where we did our initial work to support our IND. But we also are prepared to move beyond the academic facility to one that can scale with us. One of the ways to prevent these bottlenecks is to move as early as possible to a manufacturing facility that can also supply us and scale all the way to a commercial product. We’ve decided that we aren’t going to build a $200-million plant for commercial supply ourselves. We have great partners that can start working with us now and then scale with us over time.

GEN Edge: Where does the company name originate?

Lehrer: It has a lot of meaning for us internally. One connection people make, which was part of the reason for the name, is that of a graphite pencil rewriting genes. There’s also the idea of graphite being made from carbon—the element of life.

But the company name comes from Rosalind Franklin’s story. Rosalind Franklin took the famous X-ray fraction photograph that Watson and Crick used to solve the structure of DNA. She didn’t get much credit and was largely written out of the history of this discovery. Rosalind Franklin was a woman in science who didn’t get her fair shake. The crystal structure she solved before working on DNA was the atomic structure of graphite. So, it’s a connection to the origin story of DNA and a reference to Rosalind Franklin’s contributions, which have historically been neglected—much like SCD and many of the patient communities that we serve.

The post Can Graphite Bio Realize the Promise of CRISPR Gene Editing to Develop One-time Cures? appeared first on GEN - Genetic Engineering and Biotechnology News.

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“I Can’t Even Save”: Americans Are Getting Absolutely Crushed Under Enormous Debt Load

"I Can’t Even Save": Americans Are Getting Absolutely Crushed Under Enormous Debt Load

While Joe Biden insists that Americans are doing great…

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"I Can't Even Save": Americans Are Getting Absolutely Crushed Under Enormous Debt Load

While Joe Biden insists that Americans are doing great - suggesting in his State of the Union Address last week that "our economy is the envy of the world," Americans are being absolutely crushed by inflation (which the Biden admin blames on 'shrinkflation' and 'corporate greed'), and of course - crippling debt.

The signs are obvious. Last week we noted that banks' charge-offs are accelerating, and are now above pre-pandemic levels.

...and leading this increase are credit card loans - with delinquencies that haven't been this high since Q3 2011.

On top of that, while credit cards and nonfarm, nonresidential commercial real estate loans drove the quarterly increase in the noncurrent rate, residential mortgages drove the quarterly increase in the share of loans 30-89 days past due.

And while Biden and crew can spin all they want, an average of polls from RealClear Politics shows that just 40% of people approve of Biden's handling of the economy.

Crushed

On Friday, Bloomberg dug deeper into the effects of Biden's "envious" economy on Americans - specifically, how massive debt loads (credit cards and auto loans especially) are absolutely crushing people.

Two years after the Federal Reserve began hiking interest rates to tame prices, delinquency rates on credit cards and auto loans are the highest in more than a decade. For the first time on record, interest payments on those and other non-mortgage debts are as big a financial burden for US households as mortgage interest payments.

According to the report, this presents a difficult reality for millions of consumers who drive the US economy - "The era of high borrowing costs — however necessary to slow price increases — has a sting of its own that many families may feel for years to come, especially the ones that haven’t locked in cheap home loans."

The Fed, meanwhile, doesn't appear poised to cut rates until later this year.

According to a February paper from IMF and Harvard, the recent high cost of borrowing - something which isn't reflected in inflation figures, is at the heart of lackluster consumer sentiment despite inflation having moderated and a job market which has recovered (thanks to job gains almost entirely enjoyed by immigrants).

In short, the debt burden has made life under President Biden a constant struggle throughout America.

"I’m making the most money I've ever made, and I’m still living paycheck to paycheck," 40-year-old Denver resident Nikki Cimino told Bloomberg. Cimino is carrying a monthly mortgage of $1,650, and has $4,000 in credit card debt following a 2020 divorce.

Nikki CiminoPhotographer: Rachel Woolf/Bloomberg

"There's this wild disconnect between what people are experiencing and what economists are experiencing."

What's more, according to Wells Fargo, families have taken on debt at a comparatively fast rate - no doubt to sustain the same lifestyle as low rates and pandemic-era stimmies provided. In fact, it only took four years for households to set a record new debt level after paying down borrowings in 2021 when interest rates were near zero. 

Meanwhile, that increased debt load is exacerbated by credit card interest rates that have climbed to a record 22%, according to the Fed.

[P]art of the reason some Americans were able to take on a substantial load of non-mortgage debt is because they’d locked in home loans at ultra-low rates, leaving room on their balance sheets for other types of borrowing. The effective rate of interest on US mortgage debt was just 3.8% at the end of last year.

Yet the loans and interest payments can be a significant strain that shapes families’ spending choices. -Bloomberg

And of course, the highest-interest debt (credit cards) is hurting lower-income households the most, as tends to be the case.

The lowest earners also understandably had the biggest increase in credit card delinquencies.

"Many consumers are levered to the hilt — maxed out on debt and barely keeping their heads above water," Allan Schweitzer, a portfolio manager at credit-focused investment firm Beach Point Capital Management told Bloomberg. "They can dog paddle, if you will, but any uptick in unemployment or worsening of the economy could drive a pretty significant spike in defaults."

"We had more money when Trump was president," said Denise Nierzwicki, 69. She and her 72-year-old husband Paul have around $20,000 in debt spread across multiple cards - all of which have interest rates above 20%.

Denise and Paul Nierzwicki blame Biden for what they see as a gloomy economy and plan to vote for the Republican candidate in November.
Photographer: Jon Cherry/Bloomberg

During the pandemic, Denise lost her job and a business deal for a bar they owned in their hometown of Lexington, Kentucky. While they applied for Social Security to ease the pain, Denise is now working 50 hours a week at a restaurant. Despite this, they're barely scraping enough money together to service their debt.

The couple blames Biden for what they see as a gloomy economy and plans to vote for the Republican candidate in November. Denise routinely voted for Democrats up until about 2010, when she grew dissatisfied with Barack Obama’s economic stances, she said. Now, she supports Donald Trump because he lowered taxes and because of his policies on immigration. -Bloomberg

Meanwhile there's student loans - which are not able to be discharged in bankruptcy.

"I can't even save, I don't have a savings account," said 29-year-old in Columbus, Ohio resident Brittany Walling - who has around $80,000 in federal student loans, $20,000 in private debt from her undergraduate and graduate degrees, and $6,000 in credit card debt she accumulated over a six-month stretch in 2022 while she was unemployed.

"I just know that a lot of people are struggling, and things need to change," she told the outlet.

The only silver lining of note, according to Bloomberg, is that broad wage gains resulting in large paychecks has made it easier for people to throw money at credit card bills.

Yet, according to Wells Fargo economist Shannon Grein, "As rates rose in 2023, we avoided a slowdown due to spending that was very much tied to easy access to credit ... Now, credit has become harder to come by and more expensive."

According to Grein, the change has posed "a significant headwind to consumption."

Then there's the election

"Maybe the Fed is done hiking, but as long as rates stay on hold, you still have a passive tightening effect flowing down to the consumer and being exerted on the economy," she continued. "Those household dynamics are going to be a factor in the election this year."

Meanwhile, swing-state voters in a February Bloomberg/Morning Consult poll said they trust Trump more than Biden on interest rates and personal debt.

Reverberations

These 'headwinds' have M3 Partners' Moshin Meghji concerned.

"Any tightening there immediately hits the top line of companies," he said, noting that for heavily indebted companies that took on debt during years of easy borrowing, "there's no easy fix."

Tyler Durden Fri, 03/15/2024 - 18:00

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Sylvester researchers, collaborators call for greater investment in bereavement care

MIAMI, FLORIDA (March 15, 2024) – The public health toll from bereavement is well-documented in the medical literature, with bereaved persons at greater…

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MIAMI, FLORIDA (March 15, 2024) – The public health toll from bereavement is well-documented in the medical literature, with bereaved persons at greater risk for many adverse outcomes, including mental health challenges, decreased quality of life, health care neglect, cancer, heart disease, suicide, and death. Now, in a paper published in The Lancet Public Health, researchers sound a clarion call for greater investment, at both the community and institutional level, in establishing support for grief-related suffering.

Credit: Photo courtesy of Memorial Sloan Kettering Comprehensive Cancer Center

MIAMI, FLORIDA (March 15, 2024) – The public health toll from bereavement is well-documented in the medical literature, with bereaved persons at greater risk for many adverse outcomes, including mental health challenges, decreased quality of life, health care neglect, cancer, heart disease, suicide, and death. Now, in a paper published in The Lancet Public Health, researchers sound a clarion call for greater investment, at both the community and institutional level, in establishing support for grief-related suffering.

The authors emphasized that increased mortality worldwide caused by the COVID-19 pandemic, suicide, drug overdose, homicide, armed conflict, and terrorism have accelerated the urgency for national- and global-level frameworks to strengthen the provision of sustainable and accessible bereavement care. Unfortunately, current national and global investment in bereavement support services is woefully inadequate to address this growing public health crisis, said researchers with Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and collaborating organizations.  

They proposed a model for transitional care that involves firmly establishing bereavement support services within healthcare organizations to ensure continuity of family-centered care while bolstering community-based support through development of “compassionate communities” and a grief-informed workforce. The model highlights the responsibility of the health system to build bridges to the community that can help grievers feel held as they transition.   

The Center for the Advancement of Bereavement Care at Sylvester is advocating for precisely this model of transitional care. Wendy G. Lichtenthal, PhD, FT, FAPOS, who is Founding Director of the new Center and associate professor of public health sciences at the Miller School, noted, “We need a paradigm shift in how healthcare professionals, institutions, and systems view bereavement care. Sylvester is leading the way by investing in the establishment of this Center, which is the first to focus on bringing the transitional bereavement care model to life.”

What further distinguishes the Center is its roots in bereavement science, advancing care approaches that are both grounded in research and community-engaged.  

The authors focused on palliative care, which strives to provide a holistic approach to minimize suffering for seriously ill patients and their families, as one area where improvements are critically needed. They referenced groundbreaking reports of the Lancet Commissions on the value of global access to palliative care and pain relief that highlighted the “undeniable need for improved bereavement care delivery infrastructure.” One of those reports acknowledged that bereavement has been overlooked and called for reprioritizing social determinants of death, dying, and grief.

“Palliative care should culminate with bereavement care, both in theory and in practice,” explained Lichtenthal, who is the article’s corresponding author. “Yet, bereavement care often is under-resourced and beset with access inequities.”

Transitional bereavement care model

So, how do health systems and communities prioritize bereavement services to ensure that no bereaved individual goes without needed support? The transitional bereavement care model offers a roadmap.

“We must reposition bereavement care from an afterthought to a public health priority. Transitional bereavement care is necessary to bridge the gap in offerings between healthcare organizations and community-based bereavement services,” Lichtenthal said. “Our model calls for health systems to shore up the quality and availability of their offerings, but also recognizes that resources for bereavement care within a given healthcare institution are finite, emphasizing the need to help build communities’ capacity to support grievers.”

Key to the model, she added, is the bolstering of community-based support through development of “compassionate communities” and “upskilling” of professional services to assist those with more substantial bereavement-support needs.

The model contains these pillars:

  • Preventive bereavement care –healthcare teams engage in bereavement-conscious practices, and compassionate communities are mindful of the emotional and practical needs of dying patients’ families.
  • Ownership of bereavement care – institutions provide bereavement education for staff, risk screenings for families, outreach and counseling or grief support. Communities establish bereavement centers and “champions” to provide bereavement care at workplaces, schools, places of worship or care facilities.
  • Resource allocation for bereavement care – dedicated personnel offer universal outreach, and bereaved stakeholders provide input to identify community barriers and needed resources.
  • Upskilling of support providers – Bereavement education is integrated into training programs for health professionals, and institutions offer dedicated grief specialists. Communities have trained, accessible bereavement specialists who provide support and are educated in how to best support bereaved individuals, increasing their grief literacy.
  • Evidence-based care – bereavement care is evidence-based and features effective grief assessments, interventions, and training programs. Compassionate communities remain mindful of bereavement care needs.

Lichtenthal said the new Center will strive to materialize these pillars and aims to serve as a global model for other health organizations. She hopes the paper’s recommendations “will cultivate a bereavement-conscious and grief-informed workforce as well as grief-literate, compassionate communities and health systems that prioritize bereavement as a vital part of ethical healthcare.”

“This paper is calling for healthcare institutions to respond to their duty to care for the family beyond patients’ deaths. By investing in the creation of the Center for the Advancement of Bereavement Care, Sylvester is answering this call,” Lichtenthal said.

Follow @SylvesterCancer on X for the latest news on Sylvester’s research and care.

# # #

Article Title: Investing in bereavement care as a public health priority

DOI: 10.1016/S2468-2667(24)00030-6

Authors: The complete list of authors is included in the paper.

Funding: The authors received funding from the National Cancer Institute (P30 CA240139 Nimer) and P30 CA008748 Vickers).

Disclosures: The authors declared no competing interests.

# # #


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Separating Information From Disinformation: Threats From The AI Revolution

Separating Information From Disinformation: Threats From The AI Revolution

Authored by Per Bylund via The Mises Institute,

Artificial intelligence…

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Separating Information From Disinformation: Threats From The AI Revolution

Authored by Per Bylund via The Mises Institute,

Artificial intelligence (AI) cannot distinguish fact from fiction. It also isn’t creative or can create novel content but repeats, repackages, and reformulates what has already been said (but perhaps in new ways).

I am sure someone will disagree with the latter, perhaps pointing to the fact that AI can clearly generate, for example, new songs and lyrics. I agree with this, but it misses the point. AI produces a “new” song lyric only by drawing from the data of previous song lyrics and then uses that information (the inductively uncovered patterns in it) to generate what to us appears to be a new song (and may very well be one). However, there is no artistry in it, no creativity. It’s only a structural rehashing of what exists.

Of course, we can debate to what extent humans can think truly novel thoughts and whether human learning may be based solely or primarily on mimicry. However, even if we would—for the sake of argument—agree that all we know and do is mere reproduction, humans have limited capacity to remember exactly and will make errors. We also fill in gaps with what subjectively (not objectively) makes sense to us (Rorschach test, anyone?). Even in this very limited scenario, which I disagree with, humans generate novelty beyond what AI is able to do.

Both the inability to distinguish fact from fiction and the inductive tether to existent data patterns are problems that can be alleviated programmatically—but are open for manipulation.

Manipulation and Propaganda

When Google launched its Gemini AI in February, it immediately became clear that the AI had a woke agenda. Among other things, the AI pushed woke diversity ideals into every conceivable response and, among other things, refused to show images of white people (including when asked to produce images of the Founding Fathers).

Tech guru and Silicon Valley investor Marc Andreessen summarized it on X (formerly Twitter): “I know it’s hard to believe, but Big Tech AI generates the output it does because it is precisely executing the specific ideological, radical, biased agenda of its creators. The apparently bizarre output is 100% intended. It is working as designed.”

There is indeed a design to these AIs beyond the basic categorization and generation engines. The responses are not perfectly inductive or generative. In part, this is necessary in order to make the AI useful: filters and rules are applied to make sure that the responses that the AI generates are appropriate, fit with user expectations, and are accurate and respectful. Given the legal situation, creators of AI must also make sure that the AI does not, for example, violate intellectual property laws or engage in hate speech. AI is also designed (directed) so that it does not go haywire or offend its users (remember Tay?).

However, because such filters are applied and the “behavior” of the AI is already directed, it is easy to take it a little further. After all, when is a response too offensive versus offensive but within the limits of allowable discourse? It is a fine and difficult line that must be specified programmatically.

It also opens the possibility for steering the generated responses beyond mere quality assurance. With filters already in place, it is easy to make the AI make statements of a specific type or that nudges the user in a certain direction (in terms of selected facts, interpretations, and worldviews). It can also be used to give the AI an agenda, as Andreessen suggests, such as making it relentlessly woke.

Thus, AI can be used as an effective propaganda tool, which both the corporations creating them and the governments and agencies regulating them have recognized.

Misinformation and Error

States have long refused to admit that they benefit from and use propaganda to steer and control their subjects. This is in part because they want to maintain a veneer of legitimacy as democratic governments that govern based on (rather than shape) people’s opinions. Propaganda has a bad ring to it; it’s a means of control.

However, the state’s enemies—both domestic and foreign—are said to understand the power of propaganda and do not hesitate to use it to cause chaos in our otherwise untainted democratic society. The government must save us from such manipulation, they claim. Of course, rarely does it stop at mere defense. We saw this clearly during the covid pandemic, in which the government together with social media companies in effect outlawed expressing opinions that were not the official line (see Murthy v. Missouri).

AI is just as easy to manipulate for propaganda purposes as social media algorithms but with the added bonus that it isn’t only people’s opinions and that users tend to trust that what the AI reports is true. As we saw in the previous article on the AI revolution, this is not a valid assumption, but it is nevertheless a widely held view.

If the AI then can be instructed to not comment on certain things that the creators (or regulators) do not want people to see or learn, then it is effectively “memory holed.” This type of “unwanted” information will not spread as people will not be exposed to it—such as showing only diverse representations of the Founding Fathers (as Google’s Gemini) or presenting, for example, only Keynesian macroeconomic truths to make it appear like there is no other perspective. People don’t know what they don’t know.

Of course, nothing is to say that what is presented to the user is true. In fact, the AI itself cannot distinguish fact from truth but only generates responses according to direction and only based on whatever the AI has been fed. This leaves plenty of scope for the misrepresentation of the truth and can make the world believe outright lies. AI, therefore, can easily be used to impose control, whether it is upon a state, the subjects under its rule, or even a foreign power.

The Real Threat of AI

What, then, is the real threat of AI? As we saw in the first article, large language models will not (cannot) evolve into artificial general intelligence as there is nothing about inductive sifting through large troves of (humanly) created information that will give rise to consciousness. To be frank, we haven’t even figured out what consciousness is, so to think that we will create it (or that it will somehow emerge from algorithms discovering statistical language correlations in existing texts) is quite hyperbolic. Artificial general intelligence is still hypothetical.

As we saw in the second article, there is also no economic threat from AI. It will not make humans economically superfluous and cause mass unemployment. AI is productive capital, which therefore has value to the extent that it serves consumers by contributing to the satisfaction of their wants. Misused AI is as valuable as a misused factory—it will tend to its scrap value. However, this doesn’t mean that AI will have no impact on the economy. It will, and already has, but it is not as big in the short-term as some fear, and it is likely bigger in the long-term than we expect.

No, the real threat is AI’s impact on information. This is in part because induction is an inappropriate source of knowledge—truth and fact are not a matter of frequency or statistical probabilities. The evidence and theories of Nicolaus Copernicus and Galileo Galilei would get weeded out as improbable (false) by an AI trained on all the (best and brightest) writings on geocentrism at the time. There is no progress and no learning of new truths if we trust only historical theories and presentations of fact.

However, this problem can probably be overcome by clever programming (meaning implementing rules—and fact-based limitations—to the induction problem), at least to some extent. The greater problem is the corruption of what AI presents: the misinformation, disinformation, and malinformation that its creators and administrators, as well as governments and pressure groups, direct it to create as a means of controlling or steering public opinion or knowledge.

This is the real danger that the now-famous open letter, signed by Elon Musk, Steve Wozniak, and others, pointed to:

“Should we let machines flood our information channels with propaganda and untruth? Should we automate away all the jobs, including the fulfilling ones? Should we develop nonhuman minds that might eventually outnumber, outsmart, obsolete and replace us? Should we risk loss of control of our civilization?”

Other than the economically illiterate reference to “automat[ing] away all the jobs,” the warning is well-taken. AI will not Terminator-like start to hate us and attempt to exterminate mankind. It will not make us all into biological batteries, as in The Matrix. However, it will—especially when corrupted—misinform and mislead us, create chaos, and potentially make our lives “solitary, poor, nasty, brutish and short.”

Tyler Durden Fri, 03/15/2024 - 06:30

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