Aubrey de Grey is the Chair and Chief Science Officer of the Methuselah Foundation, a non-profit organization dedicated to combating the aging process. In this talk presented at the February Silicon Valley Transhumanist Meetup, he outlined the several most notable developments in funding and research taking place at the Methuselah Foundation in late 2007 and early 2008.

The following transcript of Aubrey de Grey’s Silicon Valley Transhumanist meetup talk has been corrected and approved by the speaker. Video is also available.

Methuselah Foundation: Early 2008 Developments

Yesterday I was in Philadelphia, and often I give talks of course to audiences that do not know my work at all, so there I could give a talk at ten minutes’ notice, because I could just give a standard talk. Of course, it would be a little bit insulting to you, most of whom I actually recognize, to just tell you stuff you already know. I thought I would try not to do that. The result is that this will probably be rather shambolic, but anyway, here I am.

What shall I talk about? Perhaps it would be useful, since the things that I can be most confident you don’t know about are the most recent things, to talk about the stuff that has been happening recently in the Methuselah Foundation and related work. I thought I would start with telling you how things went toward the end of last year, because it was really rather good news. A number of the things I am going to tell you now have not actually been publicized in press releases and stuff like that yet, but I’m not really giving away any secrets. It is all very new news, anyway.

FUNDING

The first thing that happened was that somewhat by accident, we got into a situation that very rapidly accelerated the influx of relatively small donations to the Methuselah Foundation. As many of you will probably know, we have an ongoing challenge pledge from Peter Thiel, the co-founder of PayPal, who gives us fifty cents for every dollar we get from anywhere else. That has been going okay, but it could always go better. One of our existing medium-sized donors, a guy from Texas called Mike Cooper, said he would like to give us another $25,000 in December and that he would like to do it in a manner that leveraged it more. So he said he would like to use it as a booster for the challenge pledge that already exists, turning it from a one-for-two pledge into something better. We turned it into a two-for-one pledge, basically. After this pledge is in place, anyone who comes along and gives us a dollar, we get a total of three dollars.

Well, it worked miracles. We exhausted his 25k in a week or thereabouts, and someone else came along who had given us a few thousand dollars some time ago and said he would like to do the same thing. He gave us another 25k, and we were also able to use a donation that we had been pledged last summer from Ryan Scott, who you may know. Ryan Scott is a dot com multi-millionaire who is very interested in these sorts of activities in general, and life extension in particular. He pledged us $100,000, and we used that in the same way. We are going to try and keep this sort of thing going. It seems to be a very good way to encourage donations.

The biggest things that happened toward the end of last year, a guy called Bill Liao, who is one of the founders of a European competitor to linkedin, a company called Xing, he decided to give us more than a half a million dollars—spread over six years, but that’s okay. Furthermore, it’s not in dollars. It’s in Swiss francs, so it might actually be worth something. The best piece of news of all, Peter Thiel decided to do a bit more last Christmas—he gave us a rather nice Christmas present. The current deal is that during each calendar year, he will give us a maximum of a million dollars, and so we are out to get two million dollars in that year in order to get the whole million. We only actually got about two-thirds of a million dollars, so we only got about a third of what we need to get that whole million in. But he said, “*** it, have the whole million anyway.” Something along those lines. He was sufficiently pleased with how we had been getting on, and reckoned we had done well enough.

The long and short of it is we had a rather good December. The reason I thought I would start by telling you all this is that now that we have all this money in, we can spend it on research—on getting more of the SENS plan actually started. Of course, that is my job as Chief Science Officer of the foundation, to actually make sure that the right professors are in a position to do the right work as soon as possible. Of course, to a certain extent, I have been able to do the first stages of that before the money had actually materialized. I spent most of last year, in one way or another, creating small heads of steam around the world, getting various professors to know that there might be some money to do particular things that they might be interested in doing, but not being able to tell them when it would be. There is just so far you can go with that without really pissing people off, of course. The money, having actually materialized, there is an enormous amount of work to do to sort out what is going to be done, the intellectual property assignments, things like that.

So, it has been a lot of work. But the upshot is that we will be able to initiate at least three, and perhaps even more, projects this year, over and above the two big projects that we have been doing over the past couple of years—namely, the identification of bacterial genes that can break down things that we can’t, and the relocation of mitochondrial DNA into the nucleus. Both of those projects are obviously continuing and will be growing, in terms of manpower, during this year. Those of you who have been following this work for some time will probably know about that because I talk about it quite a bit in talks. I thought I would talk a little bit, somewhat shambolicly as I said, about the things that we are currently planning to do some more of.

RESEARCH

How many people in the room have read my book already? That’s good, because I am going to give a bit of background to each of the things I will be talking about. Another thing we are lucky to do, which is part of the complex anti-cancer strategy has to do with stem cells in the blood. If we were to develop a drug that could go in and delete the genes for telomerase so that telomerase could not be turned on, and it only went to the cancer cells that were already cancerous, that would be great in that cells that need to have a bit of telomerase turned on, which includes the stem cells for all of our continuously renewing tissues like the blood, the gut, the skin, and the lung, they would be okay. Unfortunately, a very common tactic that cancers use to resist and escape certain drugs of all sorts is they figure out ways to destroy the drug or exclude it from being taken up in the first place. A minority of the cancer just won’t see the drug, and that is quite enough.

WILT

I have always felt that this approach of deleting telomerase will require us to be preemptive, and go and hit all of our cells, not just the cancer cells. That means we are going to have a problem. If we did that and did not do anything else, we would not die of cancer, but that is because we would not have time to die of cancer, because we would have died of not having any blood sometime previously. The only reason that this whole approach ever seemed reasonable is because of the possibility of stem cell therapy—the ability to put cells back into these various tissues, stem cells, so that the tissue can remain immortal and continue to produce differentiated cells of various sorts, even though each individual stem cell in the tissue is not immortal.

There are only a few tissues that we have to worry about: blood, skin, gut, lung. Blood, ostensibly, is the easiest one here, because of course replacement of stem cells in the blood is something that we have been doing medically for rather a long time. That’s what a bone marrow transplant is. There are things that make bone marrow transplants not as effective as we would like. Again, there have been some recent advances that have really helped us to become more optimistic that we can do this. One thing that was reported out of Stanford just a couple of months ago, a group found a way to remove the stem cells from bone marrow in a way that did not involve radiation. This is really important, because radiation is bad for stem cells, but it is bad for other cells as well. It is not something you want to do if you can possibly avoid it. This splendid paper reported a way of depleting the stem cells just using antibodies to a protein being expressed on those cells. This is a much gentler approach, much less likely to have major side effects than radiation. It is a major breakthrough for a whole bunch of reasons.

The process of replacing these stem cells in the bone marrow has to start somewhere. If we are taking a mouse, let alone a human, and we want to make all of the stem cells in the bone marrow telomerase knock-outs, then we can get some stem cells out and delete the telomerase genes, then check that we have made the right modifications, but in order to get the stem cells back in, we have to do more than just inject them. We have to ensure that the stem cells go into the bone marrow and actually take—they engraft. Bone marrow transplants are okay for people who are already sick—in other words, whose bone marrow stem cells are already dying, for whatever reason. But if the bone marrow cells think they are fine, it’s just that they might be at risk of becoming cancerous some decades in the future, it turns out it doesn’t work so well. Stem cells that are happy tend to like to stay where they are, in what is called the stem cell niche. They just do not get out of the way and allow other stem cells that we may have injected to replace them.

This trick of depleting the stem cells using this antibody is going to make a big difference to the ability to replace stem cells. Partly because of this new advance, and partly because of a couple other advances in the telomerase field, once thing I have decided that we need to fund is seriously careful studies on the ability of stem cells that do not express telomerase to go in and behave just as if they did have a telomerase gene. You might think, why shouldn’t they just behave the same as normal? Telomerase is only being expressed at this low level in stem cells anyway. Suffice it to say, there is a lot of literature out there that has been purporting to cast doubt on that assumption. There may be other roles that telomerase has over and above the lengthening of telomeres.

I personally think that a lot of this work has been somewhat over-interpreted, but it remains to be seen. This is partly a case of just seeing whether this particular component of the anti-cancer strategy that I have called WILT is going to work at all. Taking it forward in mice, we will be determining whether the stem cells need to be introduced into the mice when they are young—in other words, when the bone marrow has not become aged in some other way. To the extent that that might not work, we will need to determine what aspects of the stem cell environment are somehow inadequate. The good news is that there is one particular laboratory in Southern Germany that has been working in this general space for a few years. I have good relations with the professor and he is very interested in taking a slightly different tack in the direction I have just been describing to you so as to find these things out.

CD8

Another area of SENS that is completely separate from cancer is the elimination of cells that won’t die. Of course cancer is a problem of having too many cells because the cells are dividing like crazy. They are also dying like crazy, but they are dividing even more crazily. That’s what cancer is. There are other problems that are caused by cells that are actually not dividing, but they are not dying either, and they are accumulating slowly as a result. They get in the way and cause various problems just by being there.

Probably the most serious example of this is the immune system. In the immune system we have a wide range of different types of white blood cells that have different functions in protecting us from infections. They have a large number of different things to do. There is one particular type of white blood cell called a cytotoxic T lymphocyte—CD8 is the name of the protein that these cells express on the surface—that is the main problem in respect to this accumulation of cells that I mentioned.

Here is what happens: Some viruses that we get are what are called “persistent,” which means that we get this infection and the immune system brings it under control, there are no symptoms, but the immune system does not succeed in completely eliminating the virus from the body. The virus hangs out, latently, in one or two places. There is a particular family of viruses called the herpes viruses, which are particularly bad at this. Within the family of herpes viruses, there is one virus called cytomegalovirus, which used to be considered completely harmless and uninteresting from a medical point of view.

Cytomegalovirus, clinically, does not present any obvious symptoms except in people who have got advanced AIDS or other really severe problems with their immune system. It seems to be the number one reason why you have these CD8 cells accumulating in old age in most people. Most people are infected with CMV from an early age. The way it seems to work is that these CD8 cells, which are specific to CMV and are involved in controlling it, divide. They essentially get rid of a lot of the virus but not all of it, and every time that the virus tries to have another go, it gets beaten back, but it gets beaten back by another round of division of the same family of cells.

What seems to happen is a sort of somewhat variant form of what is called replicative senescence in virto—the concept that so many of you heard about from Len Hayflick fifty years ago, whereby cells end up, due to telomere shortening, getting into a state where they cannot divide anymore. Now, in the immune system, there is a lot of cell division that goes on, and for that reason, telomerase is turned on when it is needed. But, probably as a secondary anti-cancer strategy, cells in the immune system—especially CD8 cells—do not like to do that indefinitely. They get into a state where the sort of stimulus that would normally make them proliferate and turn on telomerase, only makes them proliferate and not to turn on telomerase very much. It leads to an interesting state where they will not divide at all. It will neither divide nor turn on telomerase.

There are various ways we might deal with this problem. One is to turn on telomerase for them—stimulate their telomerase. Actually, that is a method that is being explored by a very eminent professor in this area, Rita Effros at UCLA. I am a little bit worried about that, because it seems to me that this is somehow subverting what I think is likely to be an anti-cancer response. This may have side effects in terms of lymphoma, really rather rapidly. I would rather be in favor of simply getting rid of these cells. What is wrong with these cells anyway? They are not dividing, but other cells can divide instead, and carry on keeping our immune system happy. The problem is that as you get more and more of these cells that are not dividing, there is the inhibition of the proliferation of other white blood cells. There is a system in the body that keeps the total number of white blood cells of various sorts reasonably constant. There is a whole bunch of accumulating useless ones—that leaves less room for useful ones.

There is now a pretty good consensus that this plays an enormous role in the progressive decline of function of the immune system during old age, so we would really like to fix it. The very best solution would be to actually eliminate the virus—to find some way to do what the immune system is not succeeding in doing and get rid of this virus. But the immune system is very, very clever and we are not that clever yet. The cytomegalovirus in particular is also very clever. It is a very big virus with a couple hundred genes, and we really do not know half of all the tricks it uses to hang out and not be eliminated. We may find ways to eliminate it, but it is not looking like that is an approach whose time has come. The second best is to get rid of these cells that are getting in the way. There has been some good news in that area in the past year as well.

Essentially, these cells have been progressively better characterized. At first it was only possible to identify them by virtue of the fact that they had a bunch of things on their surface that a lot of other useful cells also have, but there was one gene that they did not have on their surface that the useful cells do have. In other words, it was a negative characterization of these cells. It turns out that this is a really tricky thing to use as a target—as a way of actually identifying them clinically. What you really want are things that are expressing things that useful cells like them are not expressing—and that has now been found. There are now a combination of two particular genes, one or other of which is sometimes expressed by useful cells, but both of which are not. That is going to be rather handy in developing therapies to fix this problem.

There are also improved techniques to do something called suicide gene therapy, which is essentially a system whereby you introduce a virus into the body that will go into a lot of different types of cells, and this virus encodes a gene that is really bad for cells, and kills cells. You would think that would be a bad thing to do to people, and at this point it is, but it is a technique that has actually been used in model organisms quite a lot, because what you can do is arrange that the protein that is toxic is only expressed if the virus that you have injected goes in cells that are expressing some other particular protein. Essentially you put what is called the promoter region of some other gene upstream of your toxin and that means that the toxin only gets expressed when the other gene is also being expressed. There are of course elaborations of this sort of system that can be used so that it is only turned on when there is DDP expressed, or something like that. The idea is that you can actually be pretty indiscriminate about where these viruses that are suicide packages will go, because they will do no harm in places where you do not want them to do harm. They will only blow up and kill cells that you actually want to get rid of.

THYMUS

This is conceptually a simple idea. As tends to be the way in biology, in practice it is quite messy. But, again, progress is being made in this area. The upshot is that there is a good chance that we are going to be able to fund a project starting this year that will get a good deal further towards the goal in mice of eliminating these clonal expansions of what are called anergic—essentially broken—CD8 cells. The hope certainly is that this will play a large role in rejuvenating the immune system. There is one other thing that we want to do that is also required for rejuvenating the immune system, and that is to restore the size of a very important organ in the immune system called the thymus, which is—for whatever reason—something that shrinks throughout life and gets, even by the sort of age I am, down to 10 or 15% the size that it was in early life. It is believed that this has also a rather large role to play in the increasing dysfunction of the immune system. We want to regrow the thymus as well.

AMYLOID

There are a few labs that are looking at that. There is one lab in particular that is looking at that, and is also looking at the problem of getting rid of the anergic cells. That is the lab that I am currently most interested in funding to take this whole thing forward. That is three things that we are doing. Another one is amyloid. This is the stuff in the brain that accumulates in Alzheimer’s disease, and probably plays some role in exacerbating the progression of Alzheimer’s disease. There is still a good deal of controversy as to whether that is actually true—whether it is part of the damage, or whether it is actually harmless. For a bunch of reasons, we can say that we ought to get rid of it. If it is protective, then it is protective against something else that we are also fixing independently in the SENS plan.

Amyloid in the brain in Alzheimer’s disease is the topic of some of the best news of the year in biomedical technology. This is years that has not really got out yet because it is a bit commercially sensitive, but I will tell you anyway. About nine years ago, a company in south San Francisco called Elan Pharmaceuticals discovered and published in Nature that if you make a mouse so that it gets Alzheimer’s, which mice do not normally do, you can then get rid of the amyloid that accumulates in the mouse brain by vaccination—by stimulating the immune system so that it gobbles up the amyloid. This was a bit of a surprised, because amyloid is a protein that the body makes naturally, so you would think that like any protein that we make naturally, the body would be tolerant to it. Of course, that is the problem. The body is too tolerant to it, but there are ways to manipulate the immune system to be slightly less tolerant to one thing than it otherwise might be. That is essentially what was done. It was a vaccination to make the immune system think this was a bit foreign, and to gobble the stuff up.

There was preliminary data showing that this did actually cause an improvement in the cognitive function of the mice. It was obviously a pretty high profile paper, but more than that, the people who were working on it knew that this was important to move to clinical trials as soon as possible. It is said that the FDA did not cut any corners, but all I know is it went from mice to Phase I clinical trials and Phase II clinical trials faster than I have ever heard anything go. And a good thing too, because obviously Alzheimer’s is quite bad for quite a lot of people.

The trials started in 2001. Unfortunately, it was a failure. It was a failure in what some people might think is the worst possible way. Namely, it had bad side effects. I think the worst possible failure is something that you spent ten years doing and just does not have any effects either way. This, at least, the side effects were found within one year. The side effects only affected about 5% of the patients, but that was quite enough, because the side effects were quite severe—neuronal inflammation. One could argue that they moved to clinical trials too fast. Actually, it could have been worse. They had not thought through the likely consequences of the particular manipulation to the immune system that they were doing—active vaccination. This is essentially putting the stuff that you want to be gobbled up into the brain, and letting the patient develop their own antibodies and mechanism for getting rid of the stuff.

There is an alternative type of vaccination called passive vaccination, which involves doing the actual creation of antibodies, not in the patient but in the way that we normally create antibodies in scientific work—in rabbits. Then injecting into the brain not the amyloid substance that is supposed to stimulate the immune system, but rather, putting just the antibodies in. That sometimes can be just as effective as a stimulus to the immune system, but it stimulates slightly different bits of the immune system. This is where I am saying that in some sense the rush to clinical trials may have been a bit too much of a rush, because everything I just told you in the past couple minutes was already known—that the bits of the immune system that are activated by the active approach to vaccination are known to have a risk of causing inflammation, whereas the bits that are stimulated by the passive vaccination were pretty much known not to have this problem.

However, that is all water under the bridge. Because they figured out very quickly that they really ought to have used passive vaccination, and because more or less everyone agreed with them, they managed to start another trial pretty quickly using the new protocol of passive vaccination. At the same time, incidentally, a whole bunch of other groups have been looking at other variants, using active vaccination but with tricks that stop the inflammation, things like that. None of those have gotten far enough to be reporting yet.

Here is what has happened with the second trial from Elan. They have partnered with one of the biggest pharma companies in the world—Wyeth, for what it is worth. They went through a Phase II clinical trial. Clinical trials are, like any experiment, you have to do them in such a way as not to be biased by the results. Not to have some sort of feedback where you might influence the experiment by what you expect. That is why most clinical trials are done in a manner that is called double-blinded, where the investigators do not know who is getting the drug and who is getting the placebo. Of course the patients do not know that either. In clinical trials, sometimes, you get a drug that is so unequivocally good that enough information is coming back just anecdotally that trials get what are called “prematurely unblended.” The data are analyzed at an earlier stage in the process than what was originally intended. If it is indeed confirmed that everything is completely wonderful, the trials gets abandoned and the drug gets approved and there you go.

I cannot tell you that that’s happened with respect to this drug. That did not happen. But it is only one step below that. What has happened is this. Last year they had what is called an interim peek. They had a bit of a look at what was going on, and they started Phase III at once. That is almost as rare as abandoning a trial and approving a drug. It is fantastically good news. Because it was an interim peak and the Phase II trial was still going on, they have to finish it properly. They had not unblinded it or anything. That means they cannot go public about this. One only knows about this if one reads the press releases very carefully and goes to the right conferences and talks to the right people. The long and short of it is that a lot of people are not wanting to count their chickens before they are hatched. Rightly so, because clinical trials go bad late in the process rather often. But, it’s looking good.

Why am I telling you this? I said I was going to be telling you about the sort of things that the Methuselah Foundation are trying to fund this year. The thing is that amyloid is a more general concept than Alzheimer’s. There are other tissues in which amyloid accumulates. In particular, there are other tissues in which amyloid accumulates slowly and progressively during aging. There is one important tissue, which is the pancreas. It turns out there is a different type of amyloid that is primarily composed of a different type of protein than the main component of Alzheimer’s amyloid, which accumulates in the pancreas and which has been shown quite definitively to contribute to the progression of type II diabetes because it kills islet cells. You probably know type II diabetes is a process in which initially the problem is not in the pancreas at all, but elsewhere in the body, with insulin being unable to do its job as well as it should. This is the concept of insulin resistance. The pancreas initially compensates by making more insulin, and that is why if you have got high insulin, you might have good glucose tolerance but you actually have reason to be worried, whereas what you want is to be someone like me who has perfect glucose tolerance just by having virtually no insulin at all.

The second phase of type II diabetes is where it starts to be like type I, because the pancreas maxes out, and starts getting to a point where the islet cells die of stress, so to speak. You actually have a depletion later on in type II diabetes of the ability to make enough insulin, and that is why type II diabetes accelerates. This amyloid that I have just mentioned seems to play a part in that last process. People just have not looked at the corresponding approach. They have not looked at an immunological approach to get rid of this what is called islet amyloid. They probably have not done so because nobody was quite sure yet whether it was going to work in the brain with Alzheimer’s amyloid in humans. There were other approaches that were perhaps going more promisingly against type II diabetes, for example. My feeling is at this point that probably this work is going to happen fairly soon, but that now is the time when enthusiastic professors can be found who will be interested in pushing this work forward faster than they otherwise do at this point.

There is another type of amyloid which is even more neglected and poorly understood, which derives from a protein called transferrin. Transferrin is a protein involved in thyroid hormone transport. It accumulates as amyloid in the heart, and in other places as well, but the heart is where it seems to matter particularly. It seems to be really bad for really old people. Apparently there is a lot of what is called senile systemic amyloidosis in centenarians. The heart is the tissue that is most affected in terms of loss of function. In supercentenarians, which is people who have reached the age of 110, it seems to be fantastically common. The group based in Los Angeles called the Supercentenarian Research Foundation, who are working to study what goes wrong in supercentenarians and how they manage to live as long as they do, have got to the point of being able to organize and perform autopsies on a few of the very few people who actually live that long, and more than half of those people appear to have died of senile systemic amyloidosis.

This is definitely not something that we can ignore if we want to seriously do damage to aging. Therefore, again, it is critical that we start to develop an immuno-therapeutic approach to transferrin amyloidosis with the same ideas in mind. There are some things being looked at by the one or two labs that look at this stuff, but they are a good deal more likely to have side effects. I am very keen to promote work that follows the protocols that seem to be going so far in Alzheimer’s amyloid. That is another thing that I hope we will be able to fund this year. I have a few other ideas of things we might fund that are slightly further down my list if I get another million dollars tomorrow, but for the moment, I think I’ll stop there. Thank you very much

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James Clement is the Organizer of the Silicon Valley Transhumanist Meetup.   Tremendous thanks is given to Drew Reynolds, for video recording Aubrey de Grey's speech at the Meetup, as well as transcribing same.  The original transcript and video was posted on Michael Anissimov's Accelerating Future website.