Saturday, 22 October 2016

Challenges in getting a whole-brain connectome

I've been reading about what is preventing us from getting a whole mammalian connectome scanned today. Here are links to the papers I found:

This is Kenneth Hayworth's 2012 paper describing a facility he calls, a connectome observatory. This facility he estimates can be built for about $200 million and will give us random access to any part of the brain. Scanning the entire brain will still take years though. 

(Hayworth, K. J. (2012). Electron imaging technology for whole brain neural circuit mapping. International Journal of Machine Consciousness, 4(01), 87-108.)

This paper from 2013 reviews the challenges stopping us from getting whole connectomes. I liked this paper because it described, with pictures, some of the difficulties with reconstructing connectomes from stacks of electron microscope (EM) images. E.g. if the dotted line is the plane at which the brain was sliced, it is "difficult" to tell which of the three configurations of neurons the slice represents.

The paper also has this neat graph showing the time it takes to image a brain versus to reconstruct the connectome from the images. We're talking about a 3 or more orders of magnitude difference.

(Helmstaedter, M. (2013). Cellular-resolution connectomics: challenges of dense neural circuit reconstruction. Nature methods, 10(6), 501-507.)

There's a more recent review of the challenges in acquiring a whole-brain connectome by Shawn Mikula (a contestant in the BPF prize). It seems to be his opinion (p.4, last para.) that we'll be able to close the analysis gap in the previous graph from Haelmstadedter's paper. The main computational challenge he identified is how to validate the reconstructed connectome. He says

While consensus of redundantly- and manuallyh-traced neurites and annotated synapses is one appraoch, it relies on model-based assumptions.
I'm not sure what "model-based assumptions" here means but I'm guessing he's saying that a bunch of human annotators look at a reconstruction and agree, "this looks right." Some other (better) options are:

  • Imaging a few parts of the brain at a much higher resolution (e.g. 2x2x2nm instead of 10x10x10nm) and checking that all the relevant features visible at the higher resolution also appear at the lower resolution.
  • Trace a few neurons unambiguously (e.g. by making them fluoresce) and then compare it with the tracing from the electron microscope images.

(Mikula, S. (2016). Progress towards mammalian whole-brain cellular connectomics. Frontiers in Neuroanatomy, 10, 62.)

Well, it seems like academia is making fast enough progress on studying the connectome. If you want to try your hand at reconstructing (parts of) a connectome from EM images check out the following.

The Eyewire project (videogame where the aim is to reconstruct parts of a connectome) has a Google drive with a bunch of training data i.e. EM images of a mouse retina with the neurons labelled. Here's an example training pair.

The FlyEM group at Janelia farm also publishes a bunch of images and connectome reconstructions from a fly brain. And this powerpoint presentation talks about the analysis problems they're facing as of September 2016. FYI a fly brain may be harder to analyze since it's neurites are smaller than those of a human. But hey, if you can efficiently extract a fly's connectome, you should be able to do the same for a mammal, right?

Wednesday, 23 September 2015

Dirge Without Music

I am not resigned to the shutting away of loving hearts in the hard ground.
So it is, and so it will be, for so it has been, time out of mind:
Into the darkness they go, the wise and the lovely. Crowned
With lilies and with laurel they go; but I am not resigned.

Lovers and thinkers, into the earth with you.
Be one with the dull, the indiscriminate dust.
A fragment of what you felt, of what you knew,
A formula, a phrase remains,—but the best is lost.

The answers quick and keen, the honest look, the laughter, the love,—
They are gone. They are gone to feed the roses. Elegant and curled
Is the blossom. Fragrant is the blossom. I know. But I do not approve.
More precious was the light in your eyes than all the roses in the world.

Down, down, down into the darkness of the grave
Gently they go, the beautiful, the tender, the kind;
Quietly they go, the intelligent, the witty, the brave.
I know. But I do not approve. And I am not resigned.

Edna St. Vincent Millay, “Dirge Without Music” from Collected Poems © 1928, 1955 by Edna St. Vincent Millay and Norma Millay Ellis.

Tuesday, 23 June 2015

E.S. Posthumus - Unearthed

Imagine being revived from cryostasis to the sound of this:

Welcome back from the dead.

Cryo buys me peace of mind

Perhaps we've been selling cryonics wrong. I'm signed up and feel like the reason I should have for signing up is that cryonics buys me a small, but non-zero chance at living forever. However, for years this should didn't actually result in me signing up.

Recently, though, after being made aware of this dissonance between my words and actions, I finally signed up. I'm now very glad that I did.

But it's not because I now have a shot at everlasting life.

I've always been afraid of dying: every lurch of a plane in turbulence gets my palms sweaty; every nearly-avoided mishap I encounter while driving makes me vow to drive even less than I currently do. I won't even consider going on a cruise until I learn to swim.

These and other things still scare me, but now I have hope—real and corrigible—that no matter what happens to my body, I'll still have a chance of coming back. In boardgame terms, my cryo membership buys me a saving throw for the next time I'm about to lose the game of life.

It would be nice if I could buy this peace of mind about my family and friends. If it were possible to sign them up for cryo without their knowledge, I’d probably do it so I wouldn't worry about them while I’m away from home.

I love this quote by Ben Hoffman that captures the security I feel:
Someone at dinner used the phrase "when the worms get me" and I immediately reached under my collar to make sure I was wearing my magical anti-death amulet. So glad I'm signed up for Cryonics.
Life insurance ad: "Feel relaxed until the last moment"
Life insurance ad: "Feel relaxed until the last moment"

A friend of mine mentioned that he’d consider signing up for cryonics if he could see even a mouse get cryopreserved and then resurrected. Recent results—like Mikula and Denk preserving a mouse brain, potentially for hundreds of years, and well enough to trace all the neurons in it—point to a future when those preserved brains could be scanned, uploaded, and emulated in virtual environments that are indistinguishable from the real thing.

Hopefully, before too long, cryo will be able to satisfy our concrete, immediate desire for peace of mind and also our idealistic desire for eternal life.

Tuesday, 28 April 2015

Shawn Mikula on Brain Preservation Protocols and Extensions

Here's an interview with Shawn Mikula  a neuroscientist on his recent paper in Nature Methods describing a new protocol for preserving a mouse brain such that, in principle, the entire neuronal connectome can be scanned (actually doing it using current technology would take years).

The work is exciting because it shows that in as little as 3 years, a similar protocol for humans could be devised. That'd pave the way for mind uploading and other advances in neuroscience.

Here we describe a preparation, BROPA (brain-wide reduced-osmium staining with pyrogallol-mediated amplification), that results in the preservation and staining of ultrastructural details throughout the brain at a resolution necessary for tracing neuronal processes and identifying synaptic contacts between them. Using serial block-face electron microscopy (SBEM), we tested human annotator ability to follow neural ‘wires’ reliably and over long distances as well as the ability to detect synaptic contacts. Our results suggest that the BROPA method can produce a preparation suitable for the reconstruction of neural circuits spanning an entire mouse brain

Comparison OF BROPA to the similar but older ROTO

Saturday, 25 April 2015

How to sign up for Alcor cryo

A few months ago, I signed up for Alcor's brain-only cryopreservation. The entire process took me 11 weeks from the day I started till the day I received my medical bracelet (the thing that’ll let paramedics know that your dead body should be handled by Alcor). I paid them $90 for the application fee. From now on, every year I’ll pay $530 for Alcor membership fees, and also pay $275 for my separately purchased life insurance.

This article is intended for those who already think cryopreservation is a good idea but are putting it off since they don't know exactly what needs to be done. As you'll see from the cryopreservation agreement (page 10), the procedure is still experimental so there's a good chance that you won't be revived even if you are "frozen" the moment you die.

I chose to go the neurocryopreservation route since it seems to offer better chances for a high quality preservation, and also since it will be slightly easier for your remains to be evacuated from the storage facility in case of an emergency.

The process

Fill out the Alcor membership application available at the Alcor Membership Information and Enrollment Instructions Page. You'll have to pay the application fee of $90 to continue the process by filling out your credit card details on the last page. If you want to pay in a different manner, like I did, just call them directly at 480-905-1906 and someone will take your money.

Sign the cryo contract and get it cosigned

Next Alcor'll physically mail you the cryopreservation contracts to read and sign. Since the document runs to 60 pages, you'll need about 2 hours to read through everything. Once you're done, you'll need 3 witnesses to sign the contract. If you live in California, you will NOT need a notary to sign it.

Apply for life insurance

In order to pay for my cryopreservation, I chose to use a life insurance policy. You can use the life insurance policy offered by your employer, but only if the policy is portable i.e. you can change the legal owner and the legal beneficiary of the policy to Alcor.

I simply went to the GEICO Website and looked around for a life insurance policy that didn't require me to submit to a physical exam first. I couldn't complete the application online but a representative called me and got me insured for $22.50 per month within 24 hours.

I've heard from others who are signed up for cryo that Rudi Hoffman, a financial planner, gets good life insurance deals and will also help with the paperwork.

Change the beneficiary and owner of the insurance policy to Alcor

Once you have your life insurance policy, you'll need to change the beneficiary and owner to Alcor so that they receive the benefits in the event of your death. You'll need to
  1. Request the required forms from your insurance company
  2. Fill out, return, and confirm receipt of the change of owner form first
  3. Then fill out and return the change of beneficiary form
This was the most frustrating part of the process since I had to call the insurance company weekly for more than a month to check on the status of my forms. Note that the Alcor folks will help you fill out your change of ownership and beneficiary forms. Just ask.

Receive your Alcor medallion

Once you've confirmed that your policy has been changed, let Alcor know and they'll send you a membership packet containing a necklace and a bracelet for you to wear. In case you're involved in a fatal accident, the necklace should inform paramedics of how to treat your body until Alcor arrives.

If you'll frequently be travelling outside the U.S., ask Alcor to send you a necklace that has a phone number with the American country code prefix on it.

Alcor necklace (front)

Alcor necklace (reverse)


The preceding is all you need to be fully signed up. For bonus points, you can also do the following:

  1. Get your family members to sign affidavits promising not to block Alcor’s preservation activities after you're dead.
  2. Create a trust fund for when you’re revived.

Saturday, 18 April 2015

Picking the Right Fields

One of my goals is to see the world in a hundred years from now, that is 2115. Sadly, even if I reached the maximum observed human lifespan of 122 years, I’d still only make it another 90 years.
Seeing 2115 requires three things to occur: live long enough for the right technology to be developed, make humans not have to die anymore, and avoid global catastrophic risks. Here are my very rough estimates for the minimum amount of money that needs to be spent over the next 10 years to solve each problem
  • Live long: $0.5 million
  • No death: $1MM
  • No catastrophes: greater than $10 billion

Live long enough for the right technology to be developed

I need about $50,000 annually to live a good life. This involves purchasing creature comforts and signing up for cryonics. 10 years of this gives $0.5 million. Sadly, cryonics is not yet guaranteed to work, otherwise I could just put myself to sleep right now for much less money.

Make humans not have to die anymore

I see two paths to this
  1. Suspended animation: This involves preserving the body (or at least the brain) before it is information theoretically dead. Through private conversations with researchers in chemo- and cryo-preservation I learnt that it’ll take roughly $1 million and 3 years to develop procedures to preserve a human brain. This assumes, of course, that the vast majority of what makes us human lies in our brains.
  2. SENS research program: The SENS research foundation funds a research program at many different universities to cure aging by reversing the cellular damage that accumulates over our lifetimes. Their founder estimates that it’ll take $200 million to $1 billion dollars over 10 years to make the fastest progress on solving the problem of death.

Avoid global catastrophic risks

The few risks I looked into all would cost more than $10 billion over the next 10 years to avert. For instance, the 2015 U.S. budget has $1.6 billion for nuclear non-proliferation and at least $1.2 billion for biodefense. Surprisingly, artificial intelligence risk had no estimate I could find.

Next Actions

I’ve begun working on extending my healthy life span by increasing exercise, eating better, avoiding smoking, and driving more carefully
I’m also volunteering with the Brain Preservation Foundation, which funds research into cryonics and other means of brain preservation. Hopefully we’ll spur even better preservation protocols to be developed so that within a decade far fewer people will have to die any more.
FAI research seems potentially high leverage as well despite, or maybe because of, its unknown costs.There are very few people working on the related problems now (I couldn’t even find a precise definition of control problem), and yet it requires no specialized equipment, just a brain and an Internet connection. This suggests that trying to solve FAI-related problems could be unusually useful.

Sunday, 29 March 2015

I suspect that a lot of people will be opposed or indifferent to the idea of life extension until such a point that the technology is incontrovertibly feasible. And by that point, there'd no longer be any need for public approval of life extension.

We in the life extension community might increase the effectiveness of our marketing by explicitly conflating life extension, healthspan extension, and the promise of experience a much, much better future. In other words, eternal life in heaven. In too many conversations once I raise the possibility of life extension, the next objections are either, Why would you want to live forever as a frail old person? or How will we feed all those humans on earth if no one dies?

Perhaps I'd pique more people's interests if I led with, "the next 100 years are gonna be so great: we'll cure all diseases and have vacations on Mars and no one will have to work any more. That's why I'm working on biotechnologies that will reverse the aging in people today; so that we can all enjoy the wonderful things that are yet to come."

Saturday, 21 March 2015

For the past few months I've been thinking about ways to get artificial intelligence (AI) solve the hard problems in biology since I'm having so much trouble solving them myself. This article from the Future of Life Institute, an AI think-tank points out that others have started out with similar intentions but have come to realize that they need to take particular care not to unleash a disaster in the process:
Human reasoning is based on an understanding derived from a combination of personal experience and collective knowledge derived over generations, explains MIRI researcher Nate Soares, who trained in computer science in college. For example, you don’t have to tell managers not to risk their employees’ lives or strip mine the planet to make more paper clips. But AI paper-clip makers are vulnerable to making such mistakes because they do not share our wealth of knowledge. Even if they did, there’s no guarantee that human-engineered intelligent systems would process that knowledge the same way we would.
I'd always thought that no one would be stupid enough to attach a superintelligent computer to actuators that could seriously affect the world but I've come to see that that is naive. The moment an AI is shown to be successful in a small field, it will almost instantly be given greater and greater responsibilities so that its owners can reap maximum rewards. 

Tuesday, 6 January 2015

Here's a 40 minute video from the Alcor Conference in 2006 giving a nice, straight-to-the-point overview of the process (and current state-of-the-art) of cryopreservation. It also explains the reasons why cryonics is thought to be a reasonable means of reaching the far future.

Alcor Conference 2006 - Brian Wowk, Ph.D. - The Cryobiological Basis of Cryonics (42 min) from Alcor Life Extension Foundation on Vimeo.