Abraxis Bio Up Big on News

The stockprice of Abraxis BioSciences [ABBI], a component of the Edwards' Real Nanotech Index (ERNI), is up over 10% today on some bullish news. European drug giant AstraZeneca will pay Abraxis $200 million for the right to co-promote cancer drug Abraxane within the U.S. for the next five years. This will approximately double the current sales force for Abraxane. Separately, Abraxis will pay AstraZeneca $350 million for its U.S. analgesics and anesthetic products business, mostly various formulations of lidocaine, morphine, and similar stuff.

On Tuesday, Abraxis announced that it had purchase a pharmaceutical plant in Puerto Rico from Pfizer. The plant, which is compliant with U.S. and European regulations, will be used to manufacture Abraxane. Abraxis will lease part of the plant back to Pfizer for their Celebrex drug.

Abraxis and its CEO, Patrick Soon-Shiong, have been controversial for a number of reasons, but they just keep on trucking.

ERNI Starting to Run

(click to enlarge image)

The Edward’s Real Nanotech Index (ERNI) is over 10% since its inception on 2/17/07 and almost half of that run came in the last week. By contrast, the NASDAQ composite is only up 2.5% over that period. Its beginning to look like the markets will indeed value nanotech stocks as a separate class. Of course, it may also merely reflect the fact that the stocks of these companies, which are mostly very small, are more volatile than the market at large. In which case, we would expect ERNI to sell off faster than the market in a downturn. No doubt we will eventually get the chance to see if that’s the case.

The only stocks that actually lost ground last week were Harris & Harris, off 60 cents to 13.51, and JMAR Technologies, off a penny. The big gainers in percentage terms were Raymor, up 31% cents to $1.35 per share and Arrowhead Research, up 16% to 6.46. I saw not specific news that would account for either increase.

American Pharmaceuticals Partners has undergone a name change as the result of its merger with American Bioscience. It is now called Abraxis BioScience and the ticker has been changed to ABBI. The name change is reflected in today’s chart but does not represent any rearrangement of the index, itself.

M.M. Buckner wins the Philip K. Dick Award!!

M.M. Buckner has won the 2006 Philip K. Dick Award for her novel War Surf. I am so proud of her, I can barely type these words.

So what is the Philip K. Dick Award?

The Philip K. Dick Award is presented each year to the best science fiction book published originally as a paperback. Philip K. Dick, himself, was a science fiction writer who was largely unrecognized throughout most of his career, but fame finally hunted him down. He is the author of such classics as The Three Stigmata of Palmer Eldritch and Do Androids Dream of Electric Sheep?, the inspiration for the movie Bladerunner.


So who is M.M. Buckner?

M.M. Buckner is well, my friend Mary. I know her because of a shared interest in whitewater kayaking. She is a very accomplished paddler and her husband, Jack Lyle, is a hair-boater of some reknown, when he’s not out skydiving.

Despite being a very pretty lady, Mary is one of those people that you might miss in a crowded room. She hardly ever says anything and anyway she would probably be sitting in a corner reading a book. I don’t think that she’s shy so much as that she just has better things to do.

I was a Buckner fan long before she ever got published. Because I am a technophile and a scientist and because she puts a lot of nanotechnology in her novels, she lets me read her work first to make sure she gets the science part of sci-fi right. She is a consummate professional. Mary works very, very hard. Sometimes the good guy (gal) does win.

Reading Mary’s stuff for the first time was like finding out that your buddy from the Daily Planet, good old Clark Kent, was not Superman in his spare time, but Franz Kafka. How could this demure little lady possibly have this kind of stuff going on in her head? How could Mary be M.M. Buckner? It boggles the mind.

M.M. Buckner is the author of three published novels now, Hyperthought, Neurolink and War Surf. A fourth is on the way and I will get to read it long before you do. Eat your heart out.

ERNI Sleeps

(click to enlarge)

Afflicted no doubt, like its creator, with a severe case of spring fever, the Edwards’ Real Nanotech Index (ERNI) slept through the trading week ending April 14th, 2006, closing virtually unchanged. In fact, zeroing in on the individual components, there was really no significant moves in anything. Scanning the news background, none of the companies announced anything of note. Sometimes, there really is no news to report.

The weather is so nice, I think I’ll just go sit on my front porch and watch the grass grow…

Earthquake

Earthquakes and hurricanes are big obvious traumatic events that are reported widely. Today is the 100th anniversary of the earthquake and fire that nearly destroyed San Francisco. That lovely city, of course, has been reborn. Another great city, New Orleans, today still lays prostrate from a different yet equally awesome force of nature May New Orleans’ citizens find within themselves the resolve to rebuild (because it’s plain that for all the fine promises made, the government ain’t gonna do much). The significance of events like hurricanes and earthquakes is easy to understand and difficult to miss. But in any given year, there are many, many significant events that are little noted at the time, because their importance doesn’t become clear for years to come.

On September 18, 1991, the Massachusetts Institute of Technology awarded the degree of Doctor of Philosophy to K. Eric Drexler in “molecular nanotechnology.” This degree was very peculiar because, at that time, MIT had no department of nanotechnology and, in fact, offered no degree program or even courses in the subject. In a very real sense, the whole concept of nanotechnology was invented by Drexler himself and popularized through his book, The Engines of Creation, published in 1986. Not that there wasn’t a lot of research on tiny, nanoscale objects that preceded Drexler. Of course there was, but research on these objects was labeled chemistry or physics or biotechnology or materials sciences. Drexler’s singular accomplishment was to recognize that these amounted to all one subject at the nanoscale. The publication of Engines of Creation was an earthquake and the awarding of his degree was in recognition of that event, an aftershock significant in itself. Drexler’s Ph.D., appropriately, was the first awarded anywhere in nanotechnology.

Yesterday, serial entrepreneur Larry Bock (founder of Nanosys) and his wife Diane made a gift to the College of Chemistry to establish an endowed chair in nanotechnology at the Berkeley campus of the University of California. Another aftershock. All across the country and across the world there are now university programs in nanotechnology and nanoscale science, and billions of dollars are being spent to establish infrastructure to make these programs viable. And yet through most of the twentieth century, a scant few years ago, a student couldn’t have pursued a degree in this field at all. Because, before Drexler, nanotechnology wasn’t recognized as a separate discipline.

A lot of people don’t like Drexler. They argue that he is arrogant, brittle, or lazy, that he hasn’t done any real science. Maybe so, but nevertheless, he has already left an impressive legacy.

Real Nanotech Index Rises

We have three dogs at home: Suzi, Harley and Shiva. Sometime I claim them and sometime they belong to my wife. As in, “Your dog, Suzi, dug up my garden again, today, Honey.”

This week, I am happy to claim the Edwards’ Real Nanotech Index (ERNI) as my dog, though it shouldn’t be called a dog as it did nicely last week, thank you very much. ERNI was up 4% last week, and back above its starting point. Standouts for the week included Raymor, whose shares now costs a whole buck, FEI and Nucryst were both up over 10%. The surge in FEI shares seems to be a reaction to Vahe Sarkissian’s resignation as chairman, president and CEO. Sometimes the market is just plain rude. CFO Raymond Link will become interim CEO. I saw no specific news on Nucryst that would account for its recent gains, which continue a trend that began in the middle of last month. Nanophase is riding higher today on a new order for and initial order architectural coatings received from an unnamed customer.

. (Click for enlarged view)

Reviews of Nanotech Pioneers

Fellow blogger Darrell Brookstein has written the first customer review of The Nanotech Pioneers: Where are they taking us? for Amazon.com. He has also posted it, almost word for word, in his blog. He calls my book the “best history of nanotechnology ever written.”

Since nanotechnology has only been called nanotechnology for twenty years, you might think that it’s a little early for a history. The technology is actually a lot older; unconscious nanotechnology was used in manufacturing items like medieval stained glass and the Vikings' carbon steel blades. Still, I did not think of Nanotech Pioneers as a history until after it was written. I guess it just came out that way because that’s the way my mind works. Only very rarely does a totally new idea appear in the world—none of us are nearly as original as we think we are. So the way to really understand a concept is to see how it has developed evolutionarily over time.

For the record, Darrell’s review was unsolicited. In giving my book to relatives, I have, however, suggested that they might just consider posting a review on Amazon. They kind of chuckle at this nervously, assuming I am kidding. Wouldn't it be kind of, um, unethical to post a review of your cousin’s, nephew’s, brother’s, father’s, son’s book? Hey, but what’s a public forum for? The political bloggers at Daily Kos (left wing) or Free Republic (right wing) have been known to get together and post 100 negative reviews of books from people they don’t like, without having first read the book. Now that’s unethical.

Though I thank Darrell for his kind words, my favorite review of the book was from my sister. Rather too personal for Amazon.com, it came in a letter. If you have never had a sister, you should adopt one. A mother’s love is unconditional, but it has an amnesiac quality that discounts it a little. She doesn’t remember the labor pains you put her through. She forgets all the bad things you ever did and exaggerates all the good things. A mother’s memory is never really very clear as regards her offspring. A sister, however, remembers with agonizing clarity every mean, nasty thing you’ve ever done to her. And she loves you anyway.

The money quote from my sister: “If your purpose in writing it was to get techno-phobes like me excited about the possibilities of nanotechnology and less afraid of it, then you did a fabulous job.”

Organ Culture

In my favorite movie of all time, Blade Runner, there is a scene in which a technician dips into a vat and pulls out a cultured eyeball. We’re not there yet, but one of these days…



Too late for me though. A couple of weeks hence, a surgeon will make a slit in my left eye and scrape out my used-up, clouded over, organic lens. In its place, he will put in a mechanical contraption, an advanced model that allows three different focal lengths. I will become a cyborg replicant. How much more appealing, though, if I could be a replicant with real organic parts?

A few years from now, I’ll have to shop for a new shoulder. Too much time spent kayaking, and racquet ball before that. Titanium is nice enough, better than what I have now, but it seems awfully cold. Cartilage and bone are conceptually more pleasing, at least until the cartilage becomes hopelessly shredded and inflamed.

The day is not far away when we can rebuild an eye or a natural shoulder. Organ culture is no longer a thing of the past, thanks in part to Anthony Atala and his colleagues at Wake Forest University. Dr. Atala has developed technology for regenerating the bladder in vitro. Cells are harvested from muscle and bladder, through biopsy and then seeded onto a preformed collagen matrix, supplied with nutrients, and allowed to grow. A few years ago, he managed to implant lab-cultured functional bladders into rats and other animals. According to an article in Voice of America, he is now implanting these bladders into humans. Actually, to be precise, he is not replacing the whole bladder, but just the biggest, bulbous part, excluding the neck.

A U.S. company called Tengion will apply to perform larger clinical tests of Atala's bladders later this year.

Unlike joints and eyes, bladders don’t usually wear out. Atala’s patients are young people aged 4 to 19, who have congenital bladder disease. With all the organs in the body that do wear out, some of which are extremely critical, like kidneys and hearts, why does Atala concentrate on the bladder? A bladder is mainly just an expandable sac, some epithelium, some muscle, not much to it. But if you’re going to learn how to do organ culture, it helps to start with something simple.

God, so the Bible tells us, made Eve from a single rib extracted from Adam. It couldn’t have been a simple task. First, there is the problem of the expansion in volume from a rib to full-grown female. That’s a lot of cell divisions. Then, you need to have a recipe for trans-differentiation, since ribs don’t have some important cell types, like nerves or endocrine tissue. Also, God had to design some new organs, like the uterus, from scratch, because women need to be more talented than men. And there were aesthetic considerations, because if Eve had turned out to be such a dog that Adam wouldn’t go out with her, the whole project might have been for naught. Genesis makes no mention of failed attempts, but the orangutan must have come from somewhere. Obviously, God was ultimately an Artist with that collagen matrix, curves in just the right places, because by now, Eve has 6 billion descendents and counting. I wonder what He did, though, with all the extra Y chromosomes?

Though God may be the master organ designer and builder, we are not there yet. It is right that we should practice on the bladder before we attempt to build a heart or kidney. But don’t worry, Atala has those organs in his sights.

The cells that Atala uses to seed his organs are essentially tissue-derived adult stem cells. As such they have already undergone many of the finite number of cell divisions that non-cancerous cells are allowed. Because the cells need to expand in number to cover the collagen matrix, more cycles of division are used up. So, in a biological sense, cultured organs may already be pretty old at the time of implantation.

How much better if we could use embryonic stem cells as starting material? If only the Bush Administration would suspend its War on Science and Truth just enough to fund embryonic stem cell research. Then maybe we could actually build a heart for the Tin Man, a cerebral cortex for the Scarecrow, or a conscience for Tom Delay… Well, scratch the latter. Some things, I fear, will always be beyond the pale for medical science. Tom will have to seek his redemption the old-fashioned way.

ERNI Flat Last Week

(click for larger image)

The Edwards Real Nanotech (ERNI) went nowhere last week but there was some movement among the components.

The biggest loser was JMAR Technologies, down about 20%. On Thursday, they held a conference call to discuss their 4th quarter and yearly loss. Ronald Walrod, JMAR’s CEO, gave a presentation that might have been titled, “Hey, Nothing’s Working Out as Planned.” He was unusually candid about how delays in product development have led to delays in product marketing and therefore hoped-for revenues. He went through a long soliloquy about how the company’s BioSentry product for water testing doesn’t really work as well as they thought it would, and how a second generation model will be needed for the most general uses.

Well, Ron, nobody ever said being a tech CEO would be a bed of roses. I applaud you for your candor, if not your company’s performance. Here’s hoping you’ll have something more positive to say next year at this time. Meanwhile, it's hard to find a good reason to buy your stock.

Elsewhere on the index, NVE stopped its slide, Nucryst broke back across its $10 IPO price and Veeco continued strong.

Today, Arrowhead Research promised to sink another $10 million into its Calandro Pharmaceutical portfolio company, which is developing RNAi therapeutics (see previous post).

The "De-Risking" of RNAi

Last week, Alnylam Pharmaceuticals announced that its researchers, in collaboration with Protiva Biotherapeutics, had demonstrated the therapeutic use of systemically delivered RNAi in non-human primates. In particular, they have shown in a Nature published paper that they could block the expression of a gene encoding apoB, which is involved in cholesterol transport. The researchers achieved a >90% reduction in apoB mRNA concentrations, a 70% reduction in protein levels, and better than a 60% reduction in cholesterol levels, with a single injection of an RNAi drug. This is better cholesterol control than one would expect with Lipitor, which is the best selling drug in the world.

Possibly even more significant is what Alnylam’s President and CEO John Manganore called the “de-risking” of RNAi. If RNAi works in primates, it will likely work in humans, making potential major pharmaceutical partners and venture capitalists a whole lot more comfortable. The prospects of RNAi type drugs as a general new class of therapeutics just took an enormous leap.

What is RNAi?

The earliest macromolecule of life (at least the earliest one that is still around), seems to have been RNA. When I was a graduate student, RNA had not yet become fully appreciated. It was known to carry the information from the genome to the ribosome where proteins were made. Other specialized RNAs performed functions as part of the ribosomes. But the proteins were presumed to be the main actors in carrying out living functions.

Now we know that RNA can do a lot of things all by itself. Given the right conditions, it can self-replicate. Some RNAs have enzymatic activity and can degrade other RNAs. RNAs also can retain spatial information and react in the manner of antibodies to antigens. RNA can bind proteins, DNA, other RNAs and even small molecules.

RNAi wasn’t discovered until a few years ago. It is an ancient, evolutionarily conserved system in which one RNA transcript regulates the expression of other transcripts, especially mRNAs. What makes the system so attractive to pharmaceutical companies is the potentially broad range in the activity of RNAi. In principle, any gene, including those of viruses, could be controlled through the use of RNA. The therapeutic potential is enormous. RNAi is also valuable as a tool for unraveling molecular biology in the development of other types of drugs.

Basically, small interfering RNAs (siRNAs) bind to the target RNA strand through strand complementarity. This triggers destruction of the now double-stranded RNA pair by an enzyme called Slicer [originally posted as "Dicer" which is a separate enzyme involved in siRNA maturation. Thanks to David Frendewey for the correction]. Thus, the therapeutic RNA takes advantage of a pre-existing system for a new purpose.

Though RNAs are a natural product, siRNAs can be chemically synthesized, which makes them cheaper and easier to purify than the protein drugs of a similar size. Also, so far RNAi does not seem to trigger immune reactions in the way that foreign proteins would. They are also easily metabolized and seem to have no significant side effects. RNAi can also be introduced into the cell on a permanent basis through the use of genetic engineering, which would allow the cell to produces its own siRNA transcripts.

Problems with RNA therapeutics

Though RNA is not inherently unstable in a chemical sense, in the real world enzymes that degrade RNA are literally everywhere: in soil, in bodily secretions, even fingerprint, and especially in serum. Stability can be increased by chemical alterations of the RNA, but any such alteration must not interfere with the recognition function of the RNA or with its degradation by Dicer, the enzyme involved ultimately in the therapeutic action.

Alnylam’s candidate siRNA therapeutic was chemically altered modestly from normal RNA. Delivery through the serum was accomplished through the use of liposomes, little lipid particles that were, in this case, targeted to the liver where apoB is formed. Another RNAi company, Calandro Pharmaceuticals, uses cyclodextrin nanoparticles to transport RNAi. Engineered virus particles could likewise be used as transport vessels.

An industry in the wings

Alnylam [ALNY: NASDAQ] is not the only company attempting to develop RNAi therapeutics. Others include Sirna Therapeutics [RNAI: NASDAQ], CytRX [CytR—NASDAQ], Nastech Pharmaceuticals [NSTK: NASDAQ] and Calandro Pharmaceuticals, which is a portfolio company or Arrowhead Research [ARWR: NASDAQ], a component of the Edwards’ Real Nanotech Index. A number of others are not publicly traded yet.