Tryggvason's Race


For reasons of respect of privacy, there are no names mentioned in this entry. There are no identifiers. There are no personal specifics; and nothing at all in the story to suggest why I tell it. Some of you will know immediately why; the vast majority of you will not. There will be no explanation, in respect to the people for whom the story means the most; but you don't really need to know why I'm telling this story, or why I wrote it all this morning. The theme of hope stands on it's own.




Adenoviruses are very simple things: a coat of protein, surrounding a wisp of DNA. They cause colds and other respiratory ailments, and generally cause a lot annoyance to most and real trouble for a few. They aren't really even, by many defintions, alive --they don't eat, they don't grow, and they can't make copies of themselves. Instead, adenoviuses, like all their viral cousins, hijack the machinery of cells and force the cells to drop the normal cell things a cell does and instead madly pump out new viruses.

A virus's DNA are the instructions force-fed to the cell to order the cell to make more viruses. The purpose of the entire rest of the virus --the purpose of all the machinery kept in the virus's spikes and arms and protein coat-- is largely to inject that DNA into the cell. The success of the adenovirus viral machinery to do this task causes humanity a lot of annoyance during cold season. Then someone had a brainstorm: if viruses were so good at injecting viral DNA sequences into cells, couldn't the viruses be re-engineered to inject beneficial DNA sequences?



In Dawn of the Coming Age I talked about the Human Genome Project, the moon shot of biology--and how perhaps, if anything, the significance of that successful effort is probably *understated*. From the knowledge and changes discussed in that prior entry, it will soon be possible to know the exact genetic basis, the exact genetic mistake, underlying a huge panopoly of inherited diseases. In Sifting Through Alphabet Soup I talked about one approach to using that knowledge --finding out the switches and gears that get messed up by that genetic mistake and making drugs to fix them. That's one strategy. The other is to fix the broken gene itself.

Some of my earliest thesis work focused on literally trying to rewrite the genetic mistakes right in place, and someday I'll write an entry about it. But a more common tactic is to insert into a cell's genome a correct copy of a broken gene, to sit side-by-side with the copy that doesn't work. The correct copy does what the broken copy of a critical gene can't do, and the cell is cured. Given what viruses actually *do* for a living is inject copies of genes, trying to use viruses to inject the genes we want injected is a pretty logical approach. And from that basis the field of viral gene therapy exploded into being. Scientists and physicans have been feverishly working on applying the techniques of viral gene therapy to hundreds of different diseases. Among them is a disease called Alport Syndrome.




Alport Syndrome is one of a wide class of diseases that come from faulty production of specific members of the collagen family of proteins. The family of collagen proteins all together play a critical role in forming the structure of the human body --collagens are the steel of the human skyscraper, forming the beams that hold up the floors and the rods that run through the re-enforced concrete. There isn't just one collagen, but dozens, mixed and twined together into ropes and strands and webs in combination with other types of collagens and countless other proteins to form all the different structures in the body, from rock-hard bone to supple cartilage to delicate eye lens tissue. A large family of different diseases come from genetic mistakes that disrupt production of one of the collagen members, the loss of any particular collagen family member leading to a different disease.

In the case of Alport Syndrome, the problem comes from errors in any one of the genes for the alpha 3, alpha 4, or alpha 5 sub-types of Type IV collagen. Errors in those genes result in a failure to produce that specific sub-type of Type IV collagen. The consequences of Alport Syndrome come from what gets buggered up because you're missing that particular specific sub-type of Type IV collagen. Basically, the effect is a bit like missing something specific in your kitchen, like, for example, tequila. You can make most things (like bread and oatmeal) just fine, but when you try to make certain things (magaritas) you have very serious problems.

The loss of Type IV Collagen's Alpha 3, 4, or 5 subunits impacts very specific tissues of the body. Type IV collagen made of subunits 3, 4, and 5 are found in the eye, the ear (the cochlea, the primary sensory organ that turns sound into nervous system impulses), the lung, testis and, most importantly, kidney. Thus, patients who have a failure to produce either the alpha 3, 4, or 5 subunits of Type IV collagen often have vision problems, hearing defects, and above all, kidney problems.

The purpose of the kidney is to filter the blood, removing excess salts, acids, and bases. The kidney is the body's primary and central means of keeping the pH and salt balance of the body in the exactingly narrow range in which the fragile brain and other organs can survive. The kidney uses a two part strategy to accomplish this task. In the first step, the kidney shoves all the blood through a speciaized filter called the glomerulus. The glomerulus keeps the blood cells, the proteins, and other huge things in the blood, while allowing all the excess water, salts, and other small molecules to pass through into the proto-urine. In the second step of kidney function, the other 90% of the kidney --the proximal and distal tubules, the loop of Henle, etc, etc, etc-- is dedicated to tweaking the proto-urine, sucking back this salt, spitting out a bit more of that salt, concentrating the urine down to conserve water, so on.

Alpha 3/4/5 Type IV collagen forms a crucial part of the filter that controls that critical first step in kidney function. Defects in Alpha 3/4/5 Type IV collagen lead, in the kidney, to severe defects in the glomerular basement membrane, screwing up normal kidney operations at that very first critical step. To handwave a complex situation, the glomerular membrane basically leaks like a sieve, blood cells and large proteins leak out of the blood and into the proto-urine, and the rest of the kidney has no means whatsoever to deal with the mass of stuff on the wrong side of the blood/urine barrier. This screws up just about everything like a stampede of cattle running through the cow-town streets. As kidney function degrades, it's ability to control body pH and salt levels fails. And as the kidney grinds to a halt, so do *you*.

Technically speaking, Alport Syndrome by itself does not kill you --it's the kidney failure that is an absolutely inevitable consequence of most forms of Alport Syndrome that *does*. Survival is not possible without functional kidneys, and the vast majority of patients with Alport Syndrome lose total kidney function. The timing is extremely variable, because the number of different ways that any of the three involved collagen subtypes get screwed up is vast --there are, after all, a lot more ways to screw up a gene than the one correct way a gene can be. Thus, some patients suffer very rapid kidney failure, while others have much slower declines. The range of speeds at which kidney function in Alports fails is so wide most medical texts don't dare quote a general life expectancy. But quickly or slow, all eventually end at the same place --total loss of kidney function.

The history of medicine is, in part, is the history of the war physicans and patients have waged against kidney failure. Before the dawn of modern medicine, kidney failure was an absolute --and swift-- death sentence. The first victories were the development of drugs that could boost and stretch out the surviving kidney function to last longer. The next step was the development of the first, incredibly crude artificial mechanical kidneys --the dialysis machines, which could strech out surviving kidney function still further. The third, and to date, most critical, was the development of successful kidney transplantation --that is, the total replacement of defective kidneys with functional ones, ones with *normal* Type IV collagen, donated by the dead --and now, also by the living. About transplants I wrote in To Juliet, and to Victory. All of these give many precious extra years to patients with kidney disease --including those with Alports. But there's catches.

The first two --drugs and dialysis-- are critically important developments because they can buy extra time for patients with kidney problems by boosting surviving kidney function. That is, however, all they can do --they do nothing to reverse the underlying progression to failure. And both do only a very crude approximate job of restoring kidney function --neither do the job anywhere near as well as the natural kidney. A good analogy is having a freak winter storm rip the roof off of your Boston house and thowing a plstic sheet overhead to patch it --the plastic sheeting is a hell of a lot better than leaving the house exposed overhead to open sky, but you're still going to be cold, wet, and miserable. While the dialysis machine is certainly better than death, and while dialysis gets better with each passing year, in many cases even *with* dialysis patients remain very, very sick. Not to mention being chained to a dialysis machine for multiple hours a day does drastic things to one's lifestyle. In general, dialysis is not considered by physicians a cure but merely a way of keeping patients alive while they wait in line for a spare kidney to arrive...

Transplantation *is* a cure --sorta. Transplantation provides a new, fully functional kidney --*if*, and only as long as, many things go and continue to go right. One major problem is compatability --as discussed in detail in To Juliet, and to Victory -- essentially, the problem of your own body and it's immune system deciding that the kidney from somebody else is a foreign invader that must be destroyed. In the case of kidneys, physicans have found all kinds of ways to sledgehammer the square peg of someone else's kidney into the round hole of your body. Sorta.

Kidney transplants succeed only as long as the tenuous control over this problem is maintained. We're getting better and better with each passing year in making kidney transplants last longer. But the unfortunate fact is that many patients eventually, even after transplant, find themselves back on dialysis, waiting for a second new kidney. And there are an entire host of problems associated with the sledgehammering, which we don't need to go into; and finally, specific to Alport Syndrome, in a subset of cases, for complex reasons, the patient's own body will immediately attack the new kidney.

As currently stands, drugs, dialysis, and transplant can give extra time --as much as a dozen or more years-- to patients with Alport Syndrome who might otherwise have died swiftly. What current medicine can do is a hell of a lot better than immediate death, but it's not good enough, and the quality of life given is not good enough. And that's where we return to adenoviruses, and talk about Karl Tryggvason...

Tryggvason of the Karolinska -- the institution that thette is training to become a physican at, and one of the world's great centers of medical research-- was among the men who first identified the causative errors in Alport Syndrome. He co-authored a superb summary article in the New England Journal of Medicine all about Alport Syndrome, which I can send to anyone who is interested (drop me an e-mail). And as one of the world's leading experts in the biology of the disease, he had a very simple idea: if the problem with Alport Syndrome is a broken copy of one of the Type IV collagen genes, then why not use adenoviruses to inject a *correct* copy of the gene into the affected cells? The injected cells would then grow the missing collagen, repair the membrane, and restore kidney function. And so that's what he set out to try to do.

In Heikkila et. al, (Gene Ther. 2001 Jun;8(11):882-90), Tryggvason and colleagues discuss their work trying to do just that. They made adenoviruses designed to inject the correct gene for alpha 5 Type IV collagen into cells; showed that they could in fact do this and that the newly made alpha 5 Type IV collagen would assemble properly; and further showed that if they injected these viruses into pig kidneys they could not only get the corrected gene into the right cells (the glomerular cells), the corrected protein would be assembled into the right place. In short, it was at least theoretically possible to fix the collagen defect behind Alport Syndrome. *Theoretically*.

Even though he could get the right collagen into the right place, it's not clear that it assembled into the right structure to restore normal kidney function. It's not clear if *enough* repair was made to make a clinical difference. It's not clear whether the injected cells will *keep* producing the collagen. And then there are the whole host of problems that are common to all adenovirus gene therapy systems, regardless of disease; inserting genes randomly into the genome runs the risk of inserting the gene right into the middle of some key gene --like an anti-cancer gene-- and *causing* cancer; how the immune system deals with being injected with thousands of viruses is a real problem; the efficiency of gene transfer stinks. And so on. There are a ton of problems. But problems are made to be conquered --and this is the golden age of molecular biology and medicine.

In the next few years the most powerful computers ever built by men will come online and be thrown against the problems of biology. There is more money being spent on medical research today than ever in the history of mankind. The genetic sequence of the entire human genome has been mapped in totality, and a tidal wave of tools and techniques --like those et_alii work on personally-- have allowed questions of complexity and scale to be asked that have never been possible before. The gap between Tryggvason's current work and a cure that works is not small --but the problems are well understood, and with enough time and money, they will be solved. With related work done along every other possible line of attack against Alport Syndrome --like the artificial kidney work my physican cousin Paul was involved with, trying to build dialysis machines made of specially engineered cells rather than mere crude mechanical filters-- this disease *will* be cured, given enough time --and not that much more time, at that.

Tryggvason, the scientist at the heart of this story, is also a physican. He earned his MD and his PhD long ago, and set out with his life to try to use the weapons of science and medicine to do something for the patients he swore an oath to defend. His work, or the work someone else continues from there, will someday give patients with Alport Syndrome the lifetime, the *full* lifetime, they deserve. A life free of the dialysis machine, free of the impossible wait and the deadly risks of transplant, and above all free of the all too early end. That day is coming, and it is coming soon.

I don't know if that day will come soon enough. I suppose it never does, whether in Tryggvason's field of medicine, or in mine, or in any other. But we --the physicans like thette, the researchers like et_alii and ceara, the men like Deuce and resonance42 and Tryggvason who are both; the nurses, the techicians, the engineers and developers and everyone else in every branch of the same cause: we're going to give that race everything we have.






See also Tomorrow, We Fly.