The Internet Utters Its First Word

Question: How did you become interested in computer science? 

Leonard Kleinrock: So, way back when, I was six years old reading comic books and I loved comic books. In the centerfold of the Superman comic book was a description, not a comic, but a text of how to build something called a crystal radio. And what fascinated me was that you could build it out of parts you could find in your house or on the street at no cost. I mean, I needed an empty toilet paper roll, some wire, my father’s old razor blade, a pencil lead. That was pretty much free. I needed an earphone, which I stole from the candy store’s telephone booth, and I needed something called a variable capacitor. I had no idea what that was, but I knew I could buy it down on Canal Street. 

So, my mother took me down in the subway, I walked to the first electronic shop, banged my fist on the table and I said, I need a variable capacitor. And they guy said, what size. And it blew my cover! So, I explained what I wanted before and he said, “I know just what you need.” So, he sold us, for a few pennies, this variable capacitor. I brought it home, wired it up, and I heard music coming out of the earphone. No battery, no power, basically free. Now this was clearly magic. I decided I better figure out how this works. And that’s what launched me on this career, if you will, of engineering. And I’m still trying to figure out how it works. 

Question: When did you come up with the idea of packet switching? 

Leonard Kleinrock: I went to graduate school at MIT, and there I started working for the legendary Claude Shannon, the man who invented and created Information Theory. Brilliant guy and he was then, and still is, my role model. And I noticed that all of my classmates were doing their PhD research on the area that he had created, Information Theory. And in my mind, this was a very crowded area; Shannon had done most of the easy, good work, solid work. What was left was hard and probably inconsequential, so I imagined. But I was surrounded by computers, both at MIT and at MIT Lincoln Laboratory, where I spent my summers working. And I said, one day, these computers are going to have to talk to each other. And there was no adequate way by which they could do so. So, this really challenged me. This was a good problem, it’ll probably be important, there’s a lot of low hanging fruit, let’s go for it. 

So I started working in the area, which eventually became the Internet. And what I did for my dissertation was to basically create the mathematical theory of data networks, suggested and introduced the idea of taking messages and breaking them up into fixed length blocks, we now call those things packets, and develop the underlying technology of packet switching, which now drives the internet backbone. 

Question: What was it like to send the first Internet message? 

Leonard Kleinrock: September 2, 1969, the first packet switch, we now call those thing routers, arrived in my laboratory at UCLA. It was based on a design that we had specified the manufacturer create. It arrived there on Labor Day weekend. On the Tuesday following Labor Day, we hooked that switch up to our host computer at UCLA, the host computer was basically a time-shared computer serving the Computer Science Department at UCLA.  

So, we had a switch and we had a computer. It wasn’t going anywhere, but I like to say that the infant Internet took it first breath of life. This switch, which was part of the Internet, looked out into the world it was born and saw a computer. A month later, the second node received their switch up at Stanford Research Institute, otherwise known as SRI 400 miles to the north of us at UCLA. They’re up in the Bay Area. We put a high-speed line between our switch and their switch, they connected their computer, we had our computer. And what we wanted to do was not talk from our computer through this very small two-node network to their computer. This was October 29, 1969. 

So what was the message we wanted to send? All we wanted to do was login from our computer to their computer. Now, to login, you have to type L-O-G, and that remote machine was smart enough to know what you’re trying to do, it types the I-N for you. Ready to go, Charlie Klein, my program and myself, Bill up at the other end, and we had a telephone connection so we could communicate and make sure we watched what happened. 

So we typed the “L”, and we say, “Did you get the “L”?” He says, “Got the “L”.” Got the, did you get the “O”? Got the “O”. Got the “G”? Crash! The SRI computer crashed. So the first message every on the Internet was “Lo”. As in “Lo and Behold.” We couldn’t have anticipated a shorter, more prophetic, more succinct message than “Lo.” 

Question: Did you have a sense then of the communications revolution that would result? 

Leonard Kleinrock: Two months before the September date, on July 3, 1969, a Press Release was put out of UCLA and in there, I’m quoted in writing—I’ve got a copy of the Press Release—where I do articulate the vision I had and basically what I said was that the internet would be always available, always on, everywhere, that anybody with any device could get on there anytime, and it would be invisible, just like electricity is invisible. What I did not anticipate was that my 99-year old mother would be on the Internet—and she was until she passed away two years ago. I didn’t see this social side. Our vision then was computers talking to each other and people talking to computers, but not people to people. And of course, that’s what’s driving the Internet these days. The communities that form, the Facebooks, all the social networking, all the email is about people communicating with each other. I missed that side of it.

Recorded on May 14, 2010

The centerfold of a Superman comic book inspired the inventor who sent the first-ever Internet message.

COVID and "gain of function" research: should we create monsters to prevent them?

Gain-of-function mutation research may help predict the next pandemic — or, critics argue, cause one.

Credit: Guillermo Legaria via Getty Images
Coronavirus

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

"I was intrigued," says Ron Fouchier, in his rich, Dutch-accented English, "in how little things could kill large animals and humans."

It's late evening in Rotterdam as darkness slowly drapes our Skype conversation.

This fascination led the silver-haired virologist to venture into controversial gain-of-function mutation research — work by scientists that adds abilities to pathogens, including experiments that focus on SARS and MERS, the coronavirus cousins of the COVID-19 agent.

If we are to avoid another influenza pandemic, we will need to understand the kinds of flu viruses that could cause it. Gain-of-function mutation research can help us with that, says Fouchier, by telling us what kind of mutations might allow a virus to jump across species or evolve into more virulent strains. It could help us prepare and, in doing so, save lives.

Many of his scientific peers, however, disagree; they say his experiments are not worth the risks they pose to society.

A virus and a firestorm

The Dutch virologist, based at Erasmus Medical Center in Rotterdam, caused a firestorm of controversy about a decade ago, when he and Yoshihiro Kawaoka at the University of Wisconsin-Madison announced that they had successfully mutated H5N1, a strain of bird flu, to pass through the air between ferrets, in two separate experiments. Ferrets are considered the best flu models because their respiratory systems react to the flu much like humans.

The mutations that gave the virus its ability to be airborne transmissible are gain-of-function (GOF) mutations. GOF research is when scientists purposefully cause mutations that give viruses new abilities in an attempt to better understand the pathogen. In Fouchier's experiments, they wanted to see if it could be made airborne transmissible so that they could catch potentially dangerous strains early and develop new treatments and vaccines ahead of time.

The problem is: their mutated H5N1 could also cause a pandemic if it ever left the lab. In Science magazine, Fouchier himself called it "probably one of the most dangerous viruses you can make."

Just three special traits

Recreated 1918 influenza virionsCredit: Cynthia Goldsmith / CDC / Dr. Terrence Tumpey / Public domain via Wikipedia

For H5N1, Fouchier identified five mutations that could cause three special traits needed to trigger an avian flu to become airborne in mammals. Those traits are (1) the ability to attach to cells of the throat and nose, (2) the ability to survive the colder temperatures found in those places, and (3) the ability to survive in adverse environments.

A minimum of three mutations may be all that's needed for a virus in the wild to make the leap through the air in mammals. If it does, it could spread. Fast.

Fouchier calculates the odds of this happening to be fairly low, for any given virus. Each mutation has the potential to cripple the virus on its own. They need to be perfectly aligned for the flu to jump. But these mutations can — and do — happen.

"In 2013, a new virus popped up in China," says Fouchier. "H7N9."

H7N9 is another kind of avian flu, like H5N1. The CDC considers it the most likely flu strain to cause a pandemic. In the human outbreaks that occurred between 2013 and 2015, it killed a staggering 39% of known cases; if H7N9 were to have all five of the gain-of-function mutations Fouchier had identified in his work with H5N1, it could make COVID-19 look like a kitten in comparison.

H7N9 had three of those mutations in 2013.

Gain-of-function mutation: creating our fears to (possibly) prevent them

Flu viruses are basically eight pieces of RNA wrapped up in a ball. To create the gain-of-function mutations, the research used a DNA template for each piece, called a plasmid. Making a single mutation in the plasmid is easy, Fouchier says, and it's commonly done in genetics labs.

If you insert all eight plasmids into a mammalian cell, they hijack the cell's machinery to create flu virus RNA.

"Now you can start to assemble a new virus particle in that cell," Fouchier says.

One infected cell is enough to grow many new virus particles — from one to a thousand to a million; viruses are replication machines. And because they mutate so readily during their replication, the new viruses have to be checked to make sure it only has the mutations the lab caused.

The virus then goes into the ferrets, passing through them to generate new viruses until, on the 10th generation, it infected ferrets through the air. By analyzing the virus's genes in each generation, they can figure out what exact five mutations lead to H5N1 bird flu being airborne between ferrets.

And, potentially, people.

"This work should never have been done"

The potential for the modified H5N1 strain to cause a human pandemic if it ever slipped out of containment has sparked sharp criticism and no shortage of controversy. Rutgers molecular biologist Richard Ebright summed up the far end of the opposition when he told Science that the research "should never have been done."

"When I first heard about the experiments that make highly pathogenic avian influenza transmissible," says Philip Dormitzer, vice president and chief scientific officer of viral vaccines at Pfizer, "I was interested in the science but concerned about the risks of both the viruses themselves and of the consequences of the reaction to the experiments."

In 2014, in response to researchers' fears and some lab incidents, the federal government imposed a moratorium on all GOF research, freezing the work.

Some scientists believe gain-of-function mutation experiments could be extremely valuable in understanding the potential risks we face from wild influenza strains, but only if they are done right. Dormitzer says that a careful and thoughtful examination of the issue could lead to processes that make gain-of-function mutation research with viruses safer.

But in the meantime, the moratorium stifled some research into influenzas — and coronaviruses.

The National Academy of Science whipped up some new guidelines, and in December of 2017, the call went out: GOF studies could apply to be funded again. A panel formed by Health and Human Services (HHS) would review applications and make the decision of which studies to fund.

As of right now, only Kawaoka and Fouchier's studies have been approved, getting the green light last winter. They are resuming where they left off.

Pandora's locks: how to contain gain-of-function flu

Here's the thing: the work is indeed potentially dangerous. But there are layers upon layers of safety measures at both Fouchier's and Kawaoka's labs.

"You really need to think about it like an onion," says Rebecca Moritz of the University of Wisconsin-Madison. Moritz is the select agent responsible for Kawaoka's lab. Her job is to ensure that all safety standards are met and that protocols are created and drilled; basically, she's there to prevent viruses from escaping. And this virus has some extra-special considerations.

The specific H5N1 strain Kawaoka's lab uses is on a list called the Federal Select Agent Program. Pathogens on this list need to meet special safety considerations. The GOF experiments have even more stringent guidelines because the research is deemed "dual-use research of concern."

There was debate over whether Fouchier and Kawaoka's work should even be published.

"Dual-use research of concern is legitimate research that could potentially be used for nefarious purposes," Moritz says. At one time, there was debate over whether Fouchier and Kawaoka's work should even be published.

While the insights they found would help scientists, they could also be used to create bioweapons. The papers had to pass through a review by the U.S. National Science Board for Biosecurity, but they were eventually published.

Intentional biowarfare and terrorism aside, the gain-of-function mutation flu must be contained even from accidents. At Wisconsin, that begins with the building itself. The labs are specially designed to be able to contain pathogens (BSL-3 agricultural, for you Inside Baseball types).

They are essentially an airtight cement bunker, negatively pressurized so that air will only flow into the lab in case of any breach — keeping the viruses pushed in. And all air in and out of the lap passes through multiple HEPA filters.

Inside the lab, researchers wear special protective equipment, including respirators. Anyone coming or going into the lab must go through an intricate dance involving stripping and putting on various articles of clothing and passing through showers and decontamination.

And the most dangerous parts of the experiment are performed inside primary containment. For example, a biocontainment cabinet, which acts like an extra high-security box, inside the already highly-secure lab (kind of like the radiation glove box Homer Simpson is working in during the opening credits).

"Many people behind the institution are working to make sure this research can be done safely and securely." — REBECCA MORITZ

The Federal Select Agent program can come and inspect you at any time with no warning, Moritz says. At the bare minimum, the whole thing gets shaken down every three years.

There are numerous potential dangers — a vial of virus gets dropped; a needle prick; a ferret bite — but Moritz is confident that the safety measures and guidelines will prevent any catastrophe.

"The institution and many people behind the institution are working to make sure this research can be done safely and securely," Moritz says.

No human harm has come of the work yet, but the potential for it is real.

"Nature will continue to do this"

They were dead on the beaches.

In the spring of 2014, another type of bird flu, H10N7, swept through the harbor seal population of northern Europe. Starting in Sweden, the virus moved south and west, across Denmark, Germany, and the Netherlands. It is estimated that 10% of the entire seal population was killed.

The virus's evolution could be tracked through time and space, Fouchier says, as it progressed down the coast. Natural selection pushed through gain-of-function mutations in the seals, similarly to how H5N1 evolved to better jump between ferrets in his lab — his lab which, at the time, was shuttered.

"We did our work in the lab," Fouchier says, with a high level of safety and security. "But the same thing was happening on the beach here in the Netherlands. And so you can tell me to stop doing this research, but nature will continue to do this day in, day out."

Critics argue that the knowledge gained from the experiments is either non-existent or not worth the risk; Fouchier argues that GOF experiments are the only way to learn crucial information on what makes a flu virus a pandemic candidate.

"If these three traits could be caused by hundreds of combinations of five mutations, then that increases the risk of these things happening in nature immensely," Fouchier says.

"With something as crucial as flu, we need to investigate everything that we can," Fouchier says, hoping to find "a new Achilles' heel of the flu that we can use to stop the impact of it."

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