Strange and complex behavior of frog cell blobs

A xenobot “parent,” shaped like a hungry Pac-Man (shown in red false color), created an “offspring” xenobot (green sphere) by gathering loose frog cells in its opening.

Tiny “living machines” made of frog cells can make copies of themselves. This newly discovered renewal mechanism may help create self-renewing biological machines.

According to Kirstin Petersen, an electrical and computer engineer at Cornell University who studies groups of robots, “this is an extremely exciting breakthrough.” She says self-replicating robots are a big step toward human-free systems.

Researchers described the behavior of xenobots earlier this year (SN: 3/31/21). Small clumps of skin stem cells from frog embryos knitted themselves into small spheres and started moving. Cilia, or cellular extensions, powered the xenobots around their lab dishes.

The findings are published in the Proceedings of the National Academy of Sciences on Dec. 7. The xenobots can gather loose frog cells into spheres, which then form xenobots.
The researchers call this type of movement-induced reproduction kinematic self-replication. The study's coauthor, Douglas Blackiston of Tufts University in Medford, Massachusetts, and Harvard University, says this is typical. For example, sexual reproduction requires parental sperm and egg cells. Sometimes cells split or budded off from a parent.

“This is unique,” Blackiston says. These xenobots “find loose parts in the environment and cobble them together.” This second generation of xenobots can move like their parents, Blackiston says.
The researchers discovered that spheroid xenobots could only produce one more generation before dying out. The original xenobots' shape was predicted by an artificial intelligence program, allowing for four generations of replication.

A C shape, like an openmouthed Pac-Man, was predicted to be a more efficient progenitor. When improved xenobots were let loose in a dish, they began scooping up loose cells into their gaping “mouths,” forming more sphere-shaped bots (see image below). As many as 50 cells clumped together in the opening of a parent to form a mobile offspring. A xenobot is made up of 4,000–6,000 frog cells.

Petersen likes the Xenobots' small size. “The fact that they were able to do this at such a small scale just makes it even better,” she says. Miniature xenobots could sculpt tissues for implantation or deliver therapeutics inside the body.

Beyond the xenobots' potential jobs, the research advances an important science, says study coauthor and Tufts developmental biologist Michael Levin. The science of anticipating and controlling the outcomes of complex systems, he says.

“No one could have predicted this,” Levin says. “They regularly surprise us.” Researchers can use xenobots to test the unexpected. “This is about advancing the science of being less surprised,” Levin says.

Quenched lava may have aided in the formation of long RNA strands required by primitive life.

It took a long time for life to emerge. Microbes were present 3.7 billion years ago, just a few hundred million years after the 4.5-billion-year-old Earth had cooled enough to sustain biochemistry, according to fossils, and many scientists believe RNA was the genetic material for these first species. RNA, while not as complicated as DNA, would be difficult to forge into the lengthy strands required to transmit genetic information, raising the question of how it may have originated spontaneously.

Researchers may now have a solution. They demonstrate how basaltic glasses assist individual RNA letters, also known as nucleoside triphosphates, join into strands up to 200 letters long in lab studies. The glasses are formed when lava is quenched in air or water, or when melted rock generated by asteroid strikes cools rapidly, and they would have been plentiful in the early Earth's fire and brimstone.

The outcome has caused a schism among top origin-of-life scholars. "This appears to be a great story that finally explains how nucleoside triphosphates react with each other to create RNA strands," says Thomas Carell, a scientist at Munich's Ludwig Maximilians University. However, Harvard University's Jack Szostak, an RNA expert, says he won't believe the results until the study team thoroughly describes the RNA strands.

Researchers interested in the origins of life like the idea of a primordial "RNA universe" since the molecule can perform two different functions that are essential for life. It's made up of four chemical letters, just like DNA, and can carry genetic information. RNA, like proteins, can catalyze chemical reactions that are necessary for life.

However, RNA can cause headaches. No one has yet discovered a set of plausible primordial conditions that would cause hundreds of RNA letters—each of which is a complicated molecule—to join together into strands long enough to support the intricate chemistry required to kick-start evolution.

Basaltic glasses may have played a role, according to Stephen Mojzsis, a geologist at the University of Colorado, Boulder. They're high in metals like magnesium and iron, which help to trigger a variety of chemical reactions. "Basaltic glass was omnipresent on Earth at the time," he adds.

He provided the Foundation for Applied Molecular Evolution samples of five different basalt glasses. Each sample was ground into a fine powder, sanitized, and combined with a solution of nucleoside triphosphates by molecular biologist Elisa Biondi and her colleagues. The RNA letters were unable to link up without the presence of glass powder. However, when the molecules were mixed with the glass particles, they formed long strands of hundreds of letters, according to the researchers, who published their findings in Astrobiology this week. There was no need for heat or light. Biondi explains, "All we had to do was wait." After only a day, little RNA strands produced, yet the strands continued to grow for months. Jan Paek, a molecular biologist at Firebird Biomolecular Sciences, says, "The beauty of this approach is its simplicity." "Mix the components together, wait a few days, and look for RNA."

Nonetheless, the findings pose a slew of problems. One of the questions is how nucleoside triphosphates came to be in the first place. Recent study by Biondi's colleague Steven Benner suggests that the same basaltic glasses may have aided in the creation and stabilization of individual RNA letters.

The form of the lengthy RNA strands, according to Szostak, is a significant challenge. Enzymes in modern cells ensure that most RNAs form long linear chains. RNA letters, on the other hand, can bind in complicated branching sequences. Szostak wants the researchers to reveal what kind of RNA was produced by the basaltic glasses. "It irritates me that the authors made an intriguing initial finding but then chose to follow the hype rather than the research," Szostak says.

Biondi acknowledges that her team's experiment almost probably results in some RNA branching. She does acknowledge, however, that some branched RNAs are seen in species today, and that analogous structures may have existed before the origin of life. Other studies carried out by the study also confirmed the presence of lengthy strands with connections, indicating that they are most likely linear. "It's a healthy argument," says Dieter Braun, a Ludwig Maximilian University origin-of-life chemist. "It will set off the next series of tests."

Let's take a look back at the internet's history and see where we're going — and why.

Tim Berners Lee had a problem. He was at CERN, the world's largest particle physics factory, at the time. The institute's stated goal was to study the simplest particles with the most sophisticated scientific instruments. The institute completed the LEP Tunnel in 1988, a 27 kilometer ring. This was Europe's largest civil engineering project (to study smaller particles — electrons).

The problem Tim Berners Lee found was information loss, not particle physics. CERN employed a thousand people in 1989. Due to team size and complexity, people often struggled to recall past project information. While these obstacles could be overcome, high turnover was nearly impossible. Berners Lee addressed the issue in a proposal titled ‘Information Management'.

He had an idea. Create an information management system that allowed users to access data in a decentralized manner using a new technology called ‘hypertext'.
To quote Berners Lee, his proposal was “vague but exciting...”. The paper eventually evolved into the internet we know today. Here are three popular W3C standards used by billions of people today:

(credit: CERN)

HTML (Hypertext Markup)

A web formatting language.

URI (Unique Resource Identifier)

Each web resource has its own “address”. Known as ‘a URL'.

HTTP (Hypertext Transfer Protocol)

Retrieves linked resources from across the web.

These technologies underpin all computer work. They were the seeds of our quest to reorganize information, a task as fruitful as particle physics.

Tim Berners-Lee would probably think the three decades from 1989 to 2018 were eventful. He'd be amazed by the billions, the inspiring, the novel. Unlocking innovation at CERN through ‘Information Management'.
The fictional character would probably need a drink, walk, and a few deep breaths to fully grasp the internet's impact. He'd be surprised to see a few big names in the mix.

Then he'd say, "Something's wrong here."

We should review the web's history before going there. Was it a success after Berners Lee made it public? Web1 and Web2: What is it about what we are doing now that so many believe we need a new one, web3?

Per Outlier Ventures' Jamie Burke:

Let's explore.

Web1: The Read-Only Web

Web1 was the digital age. We put our books, research, and lives ‘online'. The web made information retrieval easier than any filing cabinet ever. Massive amounts of data were stored online. Encyclopedias, medical records, and entire libraries were put away into floppy disks and hard drives.

In 2015, the web had around 305,500,000,000 pages of content (280 million copies of Atlas Shrugged).

Initially, one didn't expect to contribute much to this database. Web1 was an online version of the real world, but not yet a new way of using the invention.

That doesn't mean developers weren't building. The web was being advanced by great minds. Web2 was born as technology advanced.

Web2: Read-Write Web

Remember when you clicked something on a website and the whole page refreshed? Is it too early to call the mid-2000s ‘the good old days'?
Browsers improved gradually, then suddenly. AJAX calls augmented CGI scripts, and applications began sending data back and forth without disrupting the entire web page. One button to ‘digg' a post (see below). Web experiences blossomed.

In 2006, Digg was the most active ‘Web 2.0' site. (Photo: Ethereum Foundation Taylor Gerring)

Interaction was the focus of new applications. Posting, upvoting, hearting, pinning, tweeting, liking, commenting, and clapping became a lexicon of their own. It exploded in 2004. Easy ways to ‘write' on the internet grew, and continue to grow.

Facebook became a Web2 icon, where users created trillions of rows of data. Google and Amazon moved from Web1 to Web2 by better understanding users and building products and services that met their needs.

Business models based on Software-as-a-Service and then managing consumer data within them for a fee have exploded.

Web2 Emerging Issues

Unbelievably, an intriguing dilemma arose. When creating this read-write web, a non-trivial question skirted underneath the covers. Who owns it all?

A good plot line emerges. Many amazing, world-changing software products quietly lost users' data control.
For example: Facebook owns much of your social graph data. Even if you hate Facebook, you can't leave without giving up that data. There is no ‘export' or ‘exit'. The platform owns ownership.

While many companies can pull data on you, you cannot do so.

On the surface, this isn't an issue. These companies use my data better than I do! A complex group of stakeholders, each with their own goals. One is maximizing shareholder value for public companies. Tim Berners-Lee (and others) dislike the incentives created.

It's easy to see what the read-write web has allowed in retrospect. We've been given the keys to create content instead of just consume it. On Facebook and Twitter, anyone with a laptop and internet can participate. But the engagement isn't ours. Platforms own themselves.

Web3: The ‘Unmediated’ Read-Write Web

Tim Berners Lee proposed a decade ago that ‘linked data' could solve the internet's data problem.

The Web of Data also allows for new domain-specific applications. Unlike Web 2.0 mashups, Linked Data applications work with an unbound global data space. As new data sources appear on the Web, they can provide more complete answers.

At around the same time as linked data research began, Satoshi Nakamoto created Bitcoin. After ten years, it appears that Berners Lee's ideas ‘link' spiritually with cryptocurrencies.

What should Web 3 do?

Here are some quick predictions for the web's future.

Users' data:
Users own information and provide it to corporations, businesses, or services that will benefit them.

Defying censorship:

No government, company, or institution should control your access to information (1, 2, 3)

Connect users and platforms:

Create symbiotic rather than competitive relationships between users and platform creators.

Open networks:

“First, the cryptonetwork-participant contract is enforced in open source code. Their voices and exits are used to keep them in check.” Dixon, Chris (4)

Global interactivity:

Transacting value, information, or assets with anyone with internet access, anywhere, at low cost

Self-determination:

Giving you the ability to own, see, and understand your entire digital identity.

Not pull, push:

‘Push' your data to trusted sources instead of ‘pulling' it from others.

Where Does This Leave Us?

People believe web3 can help build a better, fairer system. This is not the same as equal pay or outcomes, but more equal opportunity.

It should be noted that some of these advantages have been discussed previously. Will the changes work? Will they make a difference? These unanswered questions are technical, economic, political, and philosophical. Unintended consequences are likely.

We hope Web3 is a more democratic web. And we think incentives help the user. If there’s one thing that’s on our side, it’s that open has always beaten closed, given a long enough timescale.

We are at the start. 

Madoff who?

Bernie Madoff ran the largest Ponzi scheme in history, defrauding thousands of investors over at least 17 years, and possibly longer. He pioneered electronic trading and chaired Nasdaq in the 1990s. On April 14, 2021, he died while serving a 150-year sentence for money laundering, securities fraud, and other crimes.

Understanding Madoff

Madoff claimed to generate large, steady returns through a trading strategy called split-strike conversion, but he simply deposited client funds into a single bank account and paid out existing clients. He funded redemptions by attracting new investors and their capital, but the market crashed in late 2008. He confessed to his sons, who worked at his firm, on Dec. 10, 2008. Next day, they turned him in. The fund reported $64.8 billion in client assets.

Madoff pleaded guilty to 11 federal felony counts, including securities fraud, wire fraud, mail fraud, perjury, and money laundering. Ponzi scheme became a symbol of Wall Street's greed and dishonesty before the financial crisis. Madoff was sentenced to 150 years in prison and ordered to forfeit $170 billion, but no other Wall Street figures faced legal ramifications.

Bernie Madoff's Brief Biography

Bernie Madoff was born in Queens, New York, on April 29, 1938. He began dating Ruth (née Alpern) when they were teenagers. Madoff told a journalist by phone from prison that his father's sporting goods store went bankrupt during the Korean War: "You watch your father, who you idolize, build a big business and then lose everything." Madoff was determined to achieve "lasting success" like his father "whatever it took," but his career had ups and downs.

Early Madoff investments

At 22, he started Bernard L. Madoff Investment Securities LLC. First, he traded penny stocks with $5,000 he earned installing sprinklers and as a lifeguard. Family and friends soon invested with him. Madoff's bets soured after the "Kennedy Slide" in 1962, and his father-in-law had to bail him out.

Madoff felt he wasn't part of the Wall Street in-crowd. "We weren't NYSE members," he told Fishman. "It's obvious." According to Madoff, he was a scrappy market maker. "I was happy to take the crumbs," he told Fishman, citing a client who wanted to sell eight bonds; a bigger firm would turn it down.

Recognition

Success came when he and his brother Peter built electronic trading capabilities, or "artificial intelligence," that attracted massive order flow and provided market insights. "I had all these major banks coming down, entertaining me," Madoff told Fishman. "It was mind-bending."

By the late 1980s, he and four other Wall Street mainstays processed half of the NYSE's order flow. Controversially, he paid for much of it, and by the late 1980s, Madoff was making in the vicinity of $100 million a year.  He was Nasdaq chairman from 1990 to 1993.

Madoff's Ponzi scheme

It is not certain exactly when Madoff's Ponzi scheme began. He testified in court that it began in 1991, but his account manager, Frank DiPascali, had been at the firm since 1975.

Why Madoff did the scheme is unclear. "I had enough money to support my family's lifestyle. "I don't know why," he told Fishman." Madoff could have won Wall Street's respect as a market maker and electronic trading pioneer.

Madoff told Fishman he wasn't solely responsible for the fraud. "I let myself be talked into something, and that's my fault," he said, without saying who convinced him. "I thought I could escape eventually. I thought it'd be quick, but I couldn't."

Carl Shapiro, Jeffry Picower, Stanley Chais, and Norm Levy have been linked to Bernard L. Madoff Investment Securities LLC for years. Madoff's scheme made these men hundreds of millions of dollars in the 1960s and 1970s.

Madoff told Fishman, "Everyone was greedy, everyone wanted to go on." He says the Big Four and others who pumped client funds to him, outsourcing their asset management, must have suspected his returns or should have. "How can you make 15%-18% when everyone else is making less?" said Madoff.

How Madoff Got Away with It for So Long

Madoff's high returns made clients look the other way. He deposited their money in a Chase Manhattan Bank account, which merged to become JPMorgan Chase & Co. in 2000. The bank may have made $483 million from those deposits, so it didn't investigate.

When clients redeemed their investments, Madoff funded the payouts with new capital he attracted by promising unbelievable returns and earning his victims' trust. Madoff created an image of exclusivity by turning away clients. This model let half of Madoff's investors profit. These investors must pay into a victims' fund for defrauded investors.

Madoff wooed investors with his philanthropy. He defrauded nonprofits, including the Elie Wiesel Foundation for Peace and Hadassah. He approached congregants through his friendship with J. Ezra Merkin, a synagogue officer. Madoff allegedly stole $1 billion to $2 billion from his investors.

Investors believed Madoff for several reasons:

• His public portfolio seemed to be blue-chip stocks.
• His returns were high (10-20%) but consistent and not outlandish. In a 1992 interview with Madoff, the Wall Street Journal reported: "[Madoff] insists the returns were nothing special, given that the S&P 500-stock index returned 16.3% annually from 1982 to 1992. 'I'd be surprised if anyone thought matching the S&P over 10 years was remarkable,' he says.
• "He said he was using a split-strike collar strategy. A collar protects underlying shares by purchasing an out-of-the-money put option.

SEC inquiry

The Securities and Exchange Commission had been investigating Madoff and his securities firm since 1999, which frustrated many after he was prosecuted because they felt the biggest damage could have been prevented if the initial investigations had been rigorous enough.

Harry Markopolos was a whistleblower. In 1999, he figured Madoff must be lying in an afternoon. The SEC ignored his first Madoff complaint in 2000.

Markopolos wrote to the SEC in 2005: "The largest Ponzi scheme is Madoff Securities. This case has no SEC reward, so I'm turning it in because it's the right thing to do."

Markopolos found irregularities using a "Mosaic Method." Madoff's firm claimed to be profitable even when the S&P fell, which made no mathematical sense given what he was investing in. Markopolos said Madoff Securities' "undisclosed commissions" were the biggest red flag (1 percent of the total plus 20 percent of the profits).

Markopolos concluded that "investors don't know Bernie Madoff manages their money." Markopolos learned Madoff was applying for large loans from European banks (seemingly unnecessary if Madoff's returns were high).

The regulator asked Madoff for trading account documentation in 2005, after he nearly went bankrupt due to redemptions. The SEC drafted letters to two of the firms on his six-page list but didn't send them. Diana Henriques, author of "The Wizard of Lies: Bernie Madoff and the Death of Trust," documents the episode.

In 2008, the SEC was criticized for its slow response to Madoff's fraud.

Confession, sentencing of Bernie Madoff

Bernard L. Madoff Investment Securities LLC reported 5.6% year-to-date returns in November 2008; the S&P 500 fell 39%. As the selling continued, Madoff couldn't keep up with redemption requests, and on Dec. 10, he confessed to his sons Mark and Andy, who worked at his firm. "After I told them, they left, went to a lawyer, who told them to turn in their father, and I never saw them again. 2008-12-11: Bernie Madoff arrested.

Madoff insists he acted alone, but several of his colleagues were jailed. Mark Madoff died two years after his father's fraud was exposed. Madoff's investors committed suicide. Andy Madoff died of cancer in 2014.

2009 saw Madoff's 150-year prison sentence and $170 billion forfeiture. Marshals sold his three homes and yacht. Prisoner 61727-054 at Butner Federal Correctional Institution in North Carolina.

Madoff's lawyers requested early release on February 5, 2020, claiming he has a terminal kidney disease that may kill him in 18 months. Ten years have passed since Madoff's sentencing.

Bernie Madoff's Ponzi scheme aftermath

The paper trail of victims' claims shows Madoff's complexity and size. Documents show Madoff's scam began in the 1960s. His final account statements show $47 billion in "profit" from fake trades and shady accounting.

Thousands of investors lost their life savings, and multiple stories detail their harrowing loss.

Irving Picard, a New York lawyer overseeing Madoff's bankruptcy, has helped investors. By December 2018, Picard had recovered $13.3 billion from Ponzi scheme profiteers.

A Madoff Victim Fund (MVF) was created in 2013 to help compensate Madoff's victims, but the DOJ didn't start paying out the $4 billion until late 2017. Richard Breeden, a former SEC chair who oversees the fund, said thousands of claims were from "indirect investors"

Breeden and his team had to reject many claims because they weren't direct victims. Breeden said he based most of his decisions on one simple rule: Did the person invest more than they withdrew? Breeden estimated 11,000 "feeder" investors.

Breeden wrote in a November 2018 update for the Madoff Victim Fund, "We've paid over 27,300 victims 56.65% of their losses, with thousands more to come." In December 2018, 37,011 Madoff victims in the U.S. and around the world received over $2.7 billion. Breeden said the fund expected to make "at least one more significant distribution in 2019"

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