"I did get lucky and design, from first principles, a 4-fold increase in enzyme activity once, but I am not sure that is something I could repeat."

But you do not have to repeat it. If there is even a small chance that a person trying would achieve something similar, someone with ill intent could get lucky.

1. I am just throwing numbers here, but let's say 1 out of a 1000 people is a scientist, that approximates to 7.2 millions of scientists alive.

2. Let's say one in a thousand of them are working on something that could be weaponized.

3. That leaves us at 72 thousand people.

4. Let's say one in a 1000 of them would consider releasing doomsday device if they could invent it to watch world burn, that takes it down to 72 people.

5. So we are left with 72 people who are working on something that with extraordinary lucky breakthrough could be weaponized that would weaponized if they managed to achieve that.

6. All those number above are just incredibly crude estimates, but I think they illustrate the fact that such scenario is possible.

> One is not going to be able to engineer a dangerous plague that will wipe out the human race in one shot.

I believe that what you said is true, plus we could say that the fact that we haven't been exterminated with a plague makes us not so much experienced (as a race) on how detect whenever such situation will lead to being wiped out

I feel that HIV/AIDS is our only experience, at least that I'm aware of

We haven't been eradicated before, no, but battles with things like bubonic plague and smallpox and polio (and, yes, HIV/AIDS) are likely to be good case studies for such a scenario. Bubonic plague and smallpox in particular were pretty devastating to the populations they affected.

I'm not from the field, but is it that hard, for a reasonably well funded organization, to build a safe lab ?

Holy cow yes. Sterile environments are a big deal. Try holding one for a day, let alone a work week or a year. People screw up all the time, and bacteria, being pretty much invisible, are real tough to ferret out. Let alone all the actual non-sterile stuff you want to do in one. Think a clean room with bunny suits, that is the type of environment you need just to get a start on figuring out Dr. Doom type viruses and all that awful mumbo-jumbo. It takes a lot of energy, time, and resources to just get off the ground.

I do not think you need a safe lab to produce a viable weapon grade virus.

Here is basic outline: start with existing virus that has strong desired traits and known strains that mutated to resist antibiotics. Example traits include spread model, incubation length, and lethality.

Establish or take over a remote site that has little to no interaction with outside world. Remote corners of Africa and South America come to mind, there are plenty of secret illicit drug farms in the jungle. [0]

Infect the sample population with target disease, give it a few days, and slowly start to drip in countermeasures gradually increasing the dose. Idea is similar to how diseases we get anti-biotic resistant strains in the first place - people do not complete the full course of drugs and are left with weakened, but also with a strong selective pressure that benefits against strains that have resistance against drugs person was treated with.

Take samples when you have desired output and continue with new group of people.

To account for people who are immune to a particular disease repeat this with a different disease, potentially one that can advantage of weakened immune system.

Once target disease(s) are ready distribute them in population centers.

Now there are few obvious cons I can think of:

1. If secret about this leaks out, military reaction form rest of the world would be swift.

2. Hiding something like this is hard, and get's exponentially harder as group grows.

3. There is a strong chance something like this was tried already and failed. Possibly because I am grossly underestimating immune system.

4. To keep initial phase of developing secret initial group must be small, to spread it effectively dissemination group must be large.

[0] Another potential avenue is partnership with a supportive state such as Syria, North Korea, or Iran.

Without a safe lab how do you propose those running the operation won't kill themselves?

Basic precautions like light protective wear[0] and heavy dose of anti-biotic. If that does not work - great our virus now can jump protective wear, anti-biotic is no help, and there are less lose ends. Of course there needs to be some kind of full hazmat extraction team team that understands virulence of what they are dealing with in order to clean up. In case of state with lose morals helping this might be easier because you could use prison as a site and have full hazmat personal safe from prying eyes.

[0] not a full hazmat, just some protective wear over mouth, nose, ears, and eyes.

it is impossible to build a safe lab that with a high level of assurance will produce a biogenic weapon that will kill, say, more than about 10,000 people.

> One is not going to be able to engineer a dangerous plague that will wipe out the human race in one shot. One would have to do experiments, and those experiments will be noticed, because people will get sick and die.

We should still institute safety protocols suitable for a really-bad-case scenario.