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Tag: Cell

A Cure for Diabetes

(Bear with me a bit, I promise I do get to the title eventually) One of the most formative classes I took in college was a class taught by Professor Doug Melton on stem cells. While truth be told, I’ve forgotten most of what I used to know about the growth factors and specifics of how stem cells work, the class left me with two powerful ideas.

The first is that true understanding requires you to overcome your own intellectual laziness. Its not enough to just take what a so-called expert says at face value — you should question her assumptions, her evidence, her interpretation, her controls (or lack thereof), and only after questioning these things can you properly make up your own mind. While I can’t say I’ve lived up to that challenge to the fullest extent, its been a helpful guide in my coursework and in my career as a consultant, then investor, and now entrepreneur.

The second was about the importance of personal passion as a motivating force. Professor Melton’s research and expertise into stem cells was driven in no small part by the desire to find a cure for diabetes, a condition which one of his kids suffers from. It was something which made him (and his lab) work harder at finding a way to take on the daunting task of taking stem cells and turning them into the beta islet cells in the pancreas that produce insulin. It made him advocate for the creation of the Harvard Stem Cell Institute and to strongly vocalize his opinions on legitimizing stem cell research (something which I had the pleasure of interviewing him on when I worked with Nextgen).

And, its paid off! Very recently, Melton’s lab published a paper in the journal Cell which claims to have devised a way to take stem cells and turn them into functioning beta islet cells capable of secreting insulin into the bloodstreams of diabetic mice that they’re transplanted in and reduce the high blood sugar levels that are a hallmark of the disease! While I have yet to read the paper (something I’ll try to get around to eventually) and this is still a ways off from a human therapy, its amazing to see the lab achieve this goal which seemed so challenging back when I was in college (not to mention, years earlier, when Melton first wanted to tackle the problem!)

Having met various members of the Melton lab (as well as the man himself), I can’t say how happy I am for the team and how great it is that we’ve made such a breakthrough in the fight against diabetes.

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Reading the Tea Leaves on PlayStation 4 Announcement

Sony’s announcement of the PlayStation 4 today has gotten a wide array of responses from the internet (including, amusingly, dismay at the fact that Sony never actually showed the console itself). What was interesting to me was less the console itself but what is revealed about the tech industry in the pretty big changes Sony made over the PlayStation’s previous incarnations. They give a sign of things to come as we await the “XBox 720” (or whatever they call it), Valve’s “Steambox” console, and (what I ultimately think will prevail) the next generation of mobile platform-based consoles like Green Throttle.

  • Sony switched to a more standard PC technology architecture over its old custom supercomputer-like Cell architecture. This is probably due to the increasingly ridiculous costs of putting together custom chips as well as the difficulties for developers in writing software for exotic hardware: Verge link
  • New controller that includes new interface modalities which capture some of the new types of user experiences that users have grown accustomed to from the mobile world (touch, motion) and from Microsoft’s wildly successful Kinect product via their “Eye Camera” (2 1280×800 f/2.0 cameras with 4 channel microphone array): Verge link
  • Strong emphasis during the announcement on streaming cloud gameplay: It looks like Sony is trying to make the most of its $380M acquisition of Gaikai to
    • demo service letting users try the full versions of the games immediately as opposed to after downloading a large, not always available demo
    • drive instant play for downloaded games (because you can stream the game from the cloud while it downloads in the background)
    • provide support for games for the PS3/2/1 without dedicated hardware (and maybe even non-PlayStation games on the platform?)

    Verge link

  • Focus on more social interactions via saving/streaming/uploading video of gameplay: the success of sites like Machinima hint at the types of social engagement that console gamers enjoy. So given the push in the mobile/web gaming world to “social”, it makes perfect sense for Sony to embrace this (so much so that apparently Sony will have dedicated hardware to support video compression/recording/uploading in the background) even if it means support for third party services like UStream (Verge link)
  • Second screen interactivity: The idea of the console as the be-all-end-all site of experience is now thoroughly dead. According to the announcement, the PlayStation 4 includes the ability to “stream” gameplay to handheld PlayStation Vitas (Verge link) as well as the ability to deliver special content/functionality that goes alongside content to iOS/Android phones and tablets (Verge link). A lot of parallels to Microsoft’s XBox Smart Glass announcement last year and the numerous guys trying to put together a second screen experience for TVs and set-top boxes

Regardless of if the PS4 succeeds, these are interesting changes from Sony’s usual extremely locked-down, heavily customized MO and while there are still plenty of details to be described, I think it shows just how much the rise of horizontal platforms, the boom in mobile, the maturation of the cloud as a content delivery platform, and the importance of social engagement have pervaded every element of the tech industry.

(Update: as per Pat Miller’s comments, I’ve corrected some of the previous statements I made about the PlayStation 4’s use of Gaikai technology)

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The Sickle Cell Salve

I might have been crazy late with April, but for May, my on-timeliness when it comes to the paper a month posts is returning with a vengeance.

This month’s paper from Cell (a journal I usually avoid because their papers are ridiculously long :-)) dives beneath the surface of one of the classic examples of genetics used in almost every intro-to-genetics seminar/class/textbook. As you probably know, living things typically receive two sets of genes: one from the mother and one from the father. If those two sets of genes result in the same protein, then the organism is said to be homozygous for that particular trait. Otherwise, the proper term is heterozygous. In classical genetics (i.e. what was painstakingly discovered by Gregor Mendel, the “father of genetics”), being heterozygous, to a casual observer, was usually something that could only be seen after multiple generations (or with a DNA test). This is because even though the individual has two different versions of the same gene, one of them is “dominant”, expressing itself more loudly than the other.

en93587For the mutation which causes the disease sickle cell anemia (see image to the right as to why the disease is called “sickle cell”), however, the truth was a little different. While heterozygous individuals did not suffer from the problems associated with sickle cell anemia, unlike individuals homozygous for the “normal” gene, they showed a remarkable advantage when it came to surviving infection with malaria. It is one reason scientists feel that sickle cell anemia continues to be endemic in parts of the world where malaria is still a major issue.

But, how the sickle cell disease mutation did this in heterozygotes was not well-understood. The authors for this month’s paper tried to probe one possible explanation for this using mice as an experimental system. The interesting thing that they found was that mice that were heterozygous for the sickle cell trait (HbSAD), despite having better survival against malaria than those which were homozygous for the “normal” gene (HbWT) (see the Kaplan-Meier survival curve in Figure 1A below, showing the proportion of surviving mice over time), did not have a significantly different amount of infected red blood cells (see Figure 1F below).

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So if the sickle cell gene wasn’t reducing the number of infected cells, what was causing the improvement in survival? The researchers knew that red blood cells which are heterozygous for the sickle cell trait will often “leak” an iron-containing chemical called heme into the blood stream. Because heme just floating around is toxic, the body responds to this with an enzyme called heme oxygenase-1 (HO-1) which turns toxic heme into the less toxic biliverdin and carbon monoxide (CO). The researchers considered whether or not HO-1 was responsible for the improved ability of the mice to avoid cerebral malaria. In a creative experiment, they were able to show that the sickle cell mice needed HO-1 to get their better survival – mice which were genetically engineered to be missing one copy of HO-1 (Hmox1+/-), even if they were heterozygous for the sickle cell disease, did not survive particularly well when infected (see Figure 2B below, left for the survival data).

In fact, they were even able to show that if you took mice which did not have any sickle cell trait gene (the HbWT group), and replaced their blood system using irradiation and a bone marrow transplant from a heterozygous sickle cell mouse (HbSAD), you only improve survival if the cells come from a mouse with its HO-1 genes intact (Hmox1+/+) (see Figure 4A below, right).

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So, we know HO-1 is somehow the source of the heterozygous mice’s magical ability to survive malaria. But, how? As I stated earlier, the researchers knew HO-1 produced carbon monoxide (CO) and, they were able to show that heterozygous mice with a defective HO-1 response were able to survive when given carbon monoxide (see Figure 6E below). Interestingly, exposure to carbon monoxide reduces the amount of heme floating around in the bloodstream, something which gets kicked into overdrive when malaria starts killing red blood cells left and right (see Figure 6G below), something the researchers validated when they were able to neutralize the protecting power of carbon monoxide by adding more heme back into the mouse (see Figure 6H)

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So, overall, what did I think? First the positive: these are extremely clearly designed and well-controlled experiments. I could only show a fraction of the figures in the paper, but rest assured, they were very methodical about creating positive and negative controls for all their figures and experiments which is fantastic. In particular, the use of bone marrow transplantation and genetically engineered mice to prove that HO-1 plays a key role in improving survival were creative and well-done.

What leaves me unsettled with the paper is the conclusion. The problem is that the trigger for HO-1, what the authors have shown is the reason mice which are heterozygous for sickle cell anemia survive malaria better, is heme, which happens to also be what the authors say is the cause for many of the survival complications. It’s like claiming that the best way to cure a patient of poison (heme) is to give the patient more poison (heme) because the poison somehow triggers the antidote (HO-1).

In my mind, there are two possible ways to explain the results. The first is that the authors are right and the reason for this is around the levels and timing of heme in the bloodstream. Maybe the amount of heme that the sickle cell heterozygotes have is not high enough to cause some of the malaria complications, but high enough so that HO-1 is always around. That way, if a malaria infection does happen, the HO-1 stays around and keeps the final level of heme just low enough so that problems don’t happen. The second explanation is that the authors are wrong and that the carbon monoxide that HO-1 is producing is not reducing the amount of heme directly, but indirectly by reducing the ability of the malaria parasites to kill red blood cells (the source of the extra heme). In this case, sickle cell heterozygotes have chronically higher levels of HO-1.

Both are testable hypotheses – the first can be tested by playing around with different levels of heme/HO-1 and observing how the amount of free-floating heme changes over time when mice are infected with malaria. The second can be tested by observing test tubes full of red blood cells and malaria parasites under different amounts of carbon monoxide.

In any event, I hope to see further studies in this area, especially ones which lead to more effective treatments for the many millions who are affected by malaria.

(Image Credit – Sickle Cell) (Figures from paper)

Paper: Ferreira et al., “Sickle Hemoglobin Confers Tolerance to Plasmodium Infection.” Cell 145 (Apr 2011) – doi: 10.1016/j.cell.2011.03.049

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POWER trip

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I recently read The Race for a New Game Machine, a new book which details the trials and tribulations behind the creation of the chips (which run on the POWER architecture, hence the title of this post) which powered Microsoft’s Xbox360 and Sony’s Playstation 3 next-gen gaming consoles.

The interesting thing that the book reveals is that the same IBM team responsible for designing the Playstation 3 chip (the Cell) with support from partners Sony and Toshiba was asked halfway through the Cell design process to adapt the heart of the Playstation 3 chip for the chip which would go into Microsoft’s XBox360 (the Xenon)!

Ironically, even though work on the Xbox360 started way after work on the Playstation 3’s chip, due to manufacturing issues, Microsoft was able to actually have a test chip BEFORE Sony did.

As the book was written from the perspective of David Shippy and Mickie Phipps, two the engineering leads from IBM, the reader gets a first-hand account of what it was like to be on the engineering team. While the technical details are more watered down than I would have personally liked, the book dove a lot deeper into the business/organizational side of things than I thought IBM legal would allow.

Four big lessons stood out to me after reading this:

  • Organization is important. Although ex-IBM CEO Lou Gerstner engineered one of the most storied corporate turnarounds of all time, helping to transform IBM from a failing mainframe company into a successful and well-integrated “solutions” company, Shippy and Phipps’ account reveal a deeply dysfunctional organization. Corporate groups pursued more projects than the engineering teams could support, and rival product/engineering groups refused to work together in the name of marking territory. In my mind, the Cell chip failed in its vision of being used as the new architecture for all “smart electronic devices” in no small part because of this organizational dysfunction.
  • Know the competition. One thing which stood out to me as a good bestimage practice for competitive engineering projects was the effort described in an early chapter about IBM’s attempt to predict how Intel’s chips would perform during the timeframe of the product launch. I’m not sure if this is done often in engineering efforts, but the fact that IBM tried to understand (and not undersell) the capabilities of Intel’s chips during the launch window helped give the IBM team a clear goal and set of milestones for determining success. That their chip continues to have a remarkably high operating clock speed and computing performance is a testament to the success of that effort.
  • Morale is important. If there was one feeling that the authors were able to convey in the book, it was frustration. Frustration at the organizational dysfunction which plagued IBM. Frustration at not quite ethical shenanigans that IBM played in to deliver the same processing core to two competitors. Frustration at morale-shattering layoffs and hiring freezes. It’s no secret today that IBM’s chip-making division is not the most profitable division in IBM (although this is partly because IBM relies on the division not to make profits, but to give its server products a technology advantage). IBM is certainly not doing itself any favors, then, by working its engineers to the point of exhaustion. Seeing how both authors left IBM during or shortly after this project, I can only hope that IBM has changed things, or else the world may be short yet another talented chipmaker.
  • Move like a butterfly, sting like a bee. Why did Microsoft “get the jump” on Sony, despite the latter starting far far in advance? I trace it to two things. First, immediately upon seeing an excellent new chip technology (ironically, the core processor for the Playstation 3), they seized on the opportunity. They refused to take a different chip from what they wanted, they put their money where their mouth was, and they did it as fast as they could. Second, Microsoft set up a backup manufacturing line in Singapore (at a contract chip manufacturer called Chartered). This was expensive and risky, but Microsoft realized it would be good insurance against risk at IBM’s line and a good way to quickly ramp up production. This combination of betting big, but betting smart (with a way to cover their bet if it went wrong) is a hallmark of Microsoft’s business strategy. And, in this case, they made the right call. The Xbox 360, while not selling as well as Nintendo’s Wii (which incidentally runs an IBM chip as well), has been fairly successful for Microsoft (having the highest attach rate – games sold per machine – of any console), and they had the backup plan necessary to deal with the risk that IBM’s manufacturing process would run into problems (which it ultimately did).

If you’re interested in the tears and sweat that went into designing IBM’s “PB” processing core (it’s revealed in the book that PB stands for PlayBox – an in-joke by Shippy’s team about how the technology being designed was for both the PLAYstation 3 and the xBOX), some first-hand account of how difficult it is to design next-generation semiconductor products, or how IBM got away with designing the same product for two competitors, I’d highly recommend this book.

(Image credit – book cover) (Image – Cell chip)

Book: The Race for a New Game Machine (Amazonlink)

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