Why was Andrew Grove speaking at the Society for Neuroscience?

If medicine were like chips, you could get a cure for Alzheimers by doing a 50% shrink on aspirin. Shrink it again, and you get a cure for diabetes. Shrink it again, and you get a cure for parkinson's.

Of course, it's not like that.

More complex? When is the last time you've taken a look at microprocessor schematics & circuitry? Back in 1974 when you were playing around with Radio Shack kits doesn't count.

Biology just appears complex because it's an unknown system and we have to use circuitous (no pun intended)routes of investigation and experiementation to tease the unknown apart.

I'd agree with Trivers (Genes in Conflict) that genetics is complex, but I'm not about to drop what I'm doing to study anthro cause genetics is too hard...

But circuits nowaways - may be on par with Mother Nature.

Hmmm, Parkinson's, you say?

It seems to me that a lot of people are working on a cure for Parkinson's. Some of the approaches involve embryonic stem cells, and that field is greatly hampered by government limitations and some overly restrictive patents. I didn't see that mentioned in the linked interview.

If he wants to kick some ass, that's the direction to point his foot.

Engineering vs. reverse engineering. As I understand it, that first one may look harder, but it's not.

Grove should be challenged to use his fortune to make some breakthroughs in some of the problem areas that interest him. I suspect he would be praised for establishing the Grove Institute for Research into Neurological Development.

Well put.

Also, behind the whole incorrect idea that scientific research is lagging because things aren't moving fast enough is an insinuation that the NIH doesn't care, when they are trying to be careful and are moving through many trials.

I feel for Mr. Grove, but his rant appears to be symptomatic of a culture that distrusts scientific progress.

As my grad. school roommate put it when I showed this article to him: "Sounds like someone's volunteering for human trials!" :)

I suppose we would make faster progress on curing cancer and neuron injury in humans - if we were allowed to do all of our experiments on humans.

It deeply bothers me when popular science articles say that biologists use flawed models of disease (because we're stupid, or something). Of course we use flawed models of disease. It's because the perfect models of disease (humans with the disease) are unethical to experiment with.

I'd like to see how well Intel would have been at designing better microchips if it were unethical to use microchips.

Gah. What a clueless twit.

But circuits nowaways - may be on par with Mother Nature.

Speed of a P4/Xeon ≃ 10^10 op/s
Speed of a human brain (est. equiv.) ≃ 10^22 op/s

10^22/10^10 = 10^12

The price of a half-eaten turnip nowadays - may be on par with the accumulated net worth of Warren Buffett.

critics who are fed up with biomedical research that lets paralyzed rats (but not people) walk again, that cures mouse (but not human) cancer and that lifts the fog of the rodent version of Alzheimer's but not people's

Oh come on. Is Grove really this addled? He can't seriously believe that scientists care more about rats and mice?

Here then is what Grove's contribution can be -- to volunteer as a test for invasive brain experimentation to allow those heroes he disparages to get some hands-on time with a real human model.

What a putz.

Factician: I agree wholeheartedly... society seems to view biology as "The Stupid Science" for some reason. My field is biological oceanography and fisheries science, and my best friend since 7th grade, who has a PhD in theoretical physics now, once confided in me that he can't fathom how we manage to even design experiments and research programs in such a 'noisy' environment as the ocean, with so many unknowns.

But circuits nowaways - may be on par with Mother Nature.

Ummm... what? You've got more going on in one single neuron than you have in your average microchip. Connect those neurons into a network (brain) and you've got more going on in that brain than in all the computers on the internet.

Sorry. You're off by *many* orders of magnitude.

Aren't computer whizzes simply idiot savants?

...and that's just the brain. The complexity of the biochemistry (number of simultaneous reactions and their interrelationships) going on right now in one of your liver cells is pretty mindbobbling too.

Biology -- the red-headed stepchild (who shows up to school with bruises and broken bones) of science fiction. (James Nicoll, paraphrased.)

I get a lower (still high) estimate for brain computation, though. 1e14 synapses, neural 'update' of about 1e3/second, 1e17 ops/s, maybe 1e18-1e19 bits/second.

1e22 bits/s is around the thermodynamic limit of irreversible computation you can do with the 20 Watts at 300 K of the human brain.
(joules = ln 2 * k * T * n_bits_erased, k = Boltzmann's constant, 1.38e-23)

...gg...

Maybe some people's brains are as complicated as an average microchip. Mine is not.

Another big factor is that biological systems are all non-linear and coupled. Everything engineered tends to be engineered in the linear region because it is a lot easier to design things that are linear. Linear and modular (i.e. non-coupled).

Linear complexity scales as n, non-linear complexity scales as n^y where y is greater than one.

A typical computer circuit element is connected to a few other circuit elements. A neuron is typically connected to more than 10,000.

It's too bad Grove wasted all those years playing with simple toys like microprocessors instead of trying to understand something rather more complex.

The fact that Grove is an idiot does not automatically make microprocessors simple. I mean, really.

I wish to apologize to computer whizzes and idiot savants.

Andy Grove was trained as a chemical engineer and wrote a book--ghosted?--"Only the Paranoid Survive".

The fact that Grove is an idiot does not automatically make microprocessors simple. I mean, really.

It's true. Microprocessors aren't simple. They just look simple when compared to the average liver cell.

My first reaction was also that Grove does not know what he is talking about. But I think he does have a point that the current NIH grant process stifles innovation. Currently less than the top 10 percent of NIH grants have a hope of getting funded. Put up a slightly novel idea, and chances are it will be shot to pieces by reviewers.

Pharma companies are also notorious for me-too products. Company X comes out with a cholesterol lowering drug, a year later companies Y and Z do the same... spending millions on marketing to show that they are different.

This is what the great 'road map' has bought us, baby!!!

Only results oriented research matters. If you can't get results, you're not playing by rules.

You are either riding on the translational research train, or you just don't matter.

Let us tell you what you need to get done, and now go out there and do it. Or else.

FUBAR

... once confided in me that he can't fathom how we manage to even design experiments and research programs in such a 'noisy' environment as the ocean, with so many unknowns.

Pun intentional?

Aren't computer whizzes simply idiot savants?

Yes, we are. In fact, in many cases, you can leave off the "savant" part.

In The Pipeline has a good post on it
http://pipeline.corante.com/archives/2007/11/06/andy_grove_rich_famous_…

His statements certainly were niaive but now its turned into a classic "willy measuring" contest.
I'm pretty sure that most of the advances in science recently have benefitted from the use of computers and most of the computer designers and operators have benefitted from the advances in science.
My! Aren't we all so quick to unleash the sledge hammer on the peanut?
I guess that's the problem nowadays; rather than a brief correction and agreement from like minded we have to extrapolate from one speech in order to condemn the guy's very existence and call into question the very existence of his field.

Let's not forget that whereas single function nanotechnology is current cutting edge technology, biology produced self-replicating multifunction nanotechnology back in the Archean Eon. And some of those long ago developed rather more complex interactions...

Now that you mention it, my willy is far more complex than Grove's.

Every step of the way in chip development we had the complete schematics of the current model. All Grove needs to do is supply them for the human brain and things will really take off.

My observations:

1) Increases in size or quantity aren't the same as increases in complexity.

2) Grove doesn't have the metacompetence needed to know just how little he actually knows about biology.

Sadly, I think we can see what's coming. He's going to be desperate to outwit his disease, and as it progresses, he's going to veer farther away from rationality until he jumps smack into the hands of whatever religious cult gloms onto him first. They will then parade him around as living proof that See? See?! Smarty-Pants Scientists Do Too Wuuuvvv Us until he dies and leaves them whatever dough he has left.

A regularly malfunctioning drug would be disastrous, killing people left and right, whereas a regularly crashing PC is an annoying fact of life that might upset you but seldom kill you. We swear and get on with life. Thus, it is difficult and perhaps not very meaningful to compare innovation speed in those domains.

By the by, why this boundary work, both from Grove's side and from you bio people? It seems that the history of biology has a fair share of physics or computer science people coming in and doing things of relevance to biology, from at least Gamow and onwards.

I figure there's gotta be a way for us to all get along. I look at the design and execution of Hoover Dam, Akashi Kaikyo Bridge, and I'm amazed; I could never do that.

I look at what geneticists do (my sister in law is one), and I could never do that.

I look at what the designers of the Intel Core 2 Duo do, and I could never do that.

Why can't we all just stand back and appreciate what the others do? A biologist is smarter than an computer engineer? Is a climatologist smarter than an MD?

Who cares? All I know is, if I'm driving across the Golden Gate Bridge (and I do that a lot), it means I trust the engineering behind it.

Ain't that good enough?

Just because I have a degree in Computer and Info Sciences (UCSC, 1984) doesn't mean I don't appreciate what all these other folks do. And since I'm by nature under a much larger geek umbrella, I'm also curious about what you do. I'll never fully understand it, but I'll take stabs at it.

When I stood on top of the penstocks at Hoover Dam in September, I did so with the utmost respect for what geeks before me have accomplished.

I bow my head in respect for all the geeks who came before, all the geeks to come, and all the geeks yet to be. My favorite old geek is Louis Pasteur, because of his courage, determination and brains. I bet he never dreamed there'd be SATA disk drives one day.

As far as the mouse experiments here, I sort of think what Grove is asking for is faster approval of treatments. He didn't word his POV well; and he drew a bad analogy. But I do sort of understand the frustration with the slow approval process.

relative complexity has come up quite a bit in the posts - how complicated supercomputers are vs a liver cell, etc. The real problem begins at the biophysical level though. Until Groves comes up with a computer model that can take the sequence of a protein, model the ensemble of 3d structures it will assume in its physiological environment, then accurately predict its interactions with other molecules (kd, km, kcat, agonist vs antagonist, all of the binding modes, etc) to within 10% without relying on fudge factors we're stuck with a very noisy place in which to do experiments.
I know people love "folding at home", but the force fields used for protein simulations are still much too crude to predict much of anything when it comes to drug design. And when it comes to ab initio simulations (no fudge factors allowed, all the calculations are based on general physical principles only) we can't even model model water all that well, let alone the stuff in the water.

Here is where I thought he was going with his comparison of curing disease and the number of transistors on a chip:

Embryonic stem cell research and the obstacles thrown in it's way by religious fundamentalists as a possible reason for the delay in curing disease.

Brilliant people work in all fields. Where does anyone get their idea of how quickly a particular field *should* progress?

Other than Moore's observation that "whoa, we seem to be doubling chip density every 18 months for no actual reason that I can think of", *nobody* predicted what would happen, nor does anyone validate the current rate of progress in computing: we don't exactly know what will happen and when it will happen.

Since Grove spent his career in computing, why hasn't he said or done anything about artificial intelligence research? Did he expect Perelman's solution of the Poincare conjecture in this decade? Does he have a timeline for me to stop worrying about how I can do distributed computing and leave it all to the compiler? Where is my 20GHz Core 2 Duo?

He's just understandably frustrated with his own condition, but he shouldn't be angry with the field of medicine for the wrong reason.

... expecting all diseases to be cured, particularly brain diseases, is roughly equivalent to insisting there ought to be strong AI NOW, because he SAID SO.

Even with Parkinson's, I think you have to be rather spoiled to say that.

Microprocessors are pretty simple.

Their behaviour has basically been the same from the earliest radiotubes (simple electrical gateways) into the integrated circuit.

Only materials and the way they are put together has developed based on research into materials and manufacturing processes.

Quantum computing and other ways of putting things together says more of REAL research and paradigmshifts in computing than the development of microprocessors thats is applied engineering.

Basically a contineous refinement on the same princible.

To those of you wondering why the strong response, consider the following: biological sciences and climatology are the only two sciences in existence where people from outside the field regularly trash the entire discipline. Furthermore, the professions from which these attacks come are most likely to be either Physics, engineering, or medicine.

Is it any wonder that Moore raised a few hackles?

MikeM: Great comment and sentiment.

Laserboy et al: Let's all go over to Cosmic Variance and make rude comments about dark matter and how string theory isn't science.

Sven

for a moment there, you gave me this 'orrid vision of a brain doing bobble-head thing on the back dash of my car. In fact, the vision is still there and I may be going nuts because of it.

Now I'm seeing it superimposed on all my employees... aaaaaaaah!

I've not had time to read Mr Grove's actual comments, but going on hearsay, it does appear to me that he's actually bucking for trimming the approval process, rather than taking the industry as a whole to task.

Microchips are indeed quite simple. You have a transistor - a simple binary system (on or off). Add one to it... then another and another.. it's no more complicated than it was to begin with. There's just a lot of 'em and they're hard to see. The most complicated aspect is communicating with them - telling which to turn on or off, and determining that said instruction has been carried out. It's still a polar equation.

Even DNA is more complicated than that with at least 4 possible states for each position, and it's incredibly smaller than a single cell.

I think the most idiotic thing Grove said was this:

The fundamental tenet that drives us all in the semiconductor industry is a deeply felt conviction that what matters is time to market, or time to money. But you never hear an executive from a pharmaceutical company say, "Before the end of the year I'm going to have xyz drug," the way Steve Jobs said the iPhone would be out on schedule. The heart of every high-tech executive has been, get the product into customers' hands and ramp up production. That drive is just not present in pharma; the drive to get sufficient understanding and go for it is missing.

I mean, if he doesn't work in pharma or do drug research, it's no surprise that he doesn't understand it. But does he really think the folks in pharma aren't driven to bring products to market?

Hello? McFly? As co-founder of Intel, has Grove never heard of stockholders? Investors? Profits? Share price? Return on investment?

Does he think pharma stockholders are content to throw their money away? That they don't push pharma execs to market products and make profits, exactly like Intel stockholders push Intel execs?

That's not ignorant; it's stupid.

While I must agree that the comparison between the computer industry and medical research is a stupid one and Grove does deserve to be taken to task for it, I must disagree slightly with one statement that PZ makes.

Biological research is not an exercise in applied engineering

While generally true there are a few notable exceptions where researchers are working on interfacing the human brain and nervous system with computer systems.
One might also argue that genetic modification of organisms for things like disease resistance is an example of applied bio-engineering as well, but that's more a definitional issue.

I haven't read the whole thing, but in Grove's (partial) defense, I think there is something to be said about the rate of advance in diseases--it is too slow. I am certain the world could be farther ahead with a number of changes to how science and medicine is done.

If his imprecise analogy with the computer industry is imprecise, the spirit of it is probably at least in the ballpark.

The fact that Grove is an idiot does not automatically make microprocessors simple.

True. While PZ identifies Grove's major mistake (biologists haven't nearly as much freedom of modifying the system), semiconductor manufacturing is far from simple.

Take for example Intel, which AFAIU currently works by a "tick-tock" model.

Every other year they introduce a completely new process, which may encompass anything from increasing wafer size, retooling or building a new plant, managing new lithographic processes, new and/or purer materials, and nowadays often completely remodeled and non-linear (as regards leak currents) devices and processes. As hundreds of development people work inside Intel and many more outside on standards, processes, devices, equipment, et cetera for 2 years, that would mean hundreds of man-years. The manufacturing process is fiendishly complicated, with hundreds of steps.

And every other year they introduce new architectures, which again may mean anything from completely remodeling cores, memory handling, channels et cetera, to more minor changes. But never the less will mean going from lab work up to a couple of final chip production cycles, and again means many manyears.

I'm quite sure it may rival some large biomedical efforts. But of course Grove is naive if he compares with the necessary width of medical concerns, we aren't discussing one sickness here.

You have a transistor - a simple binary system (on or off).

If it only was that simple. Granted, of all possible transistor devices the industry will only use a few models. But as they shrink, these essentially non-linear devices needs to be understood anew, often with new materials, changed parasitic properties, new failure modes, et cetera.

Then you have other active (memory cells) and passive elements that couples through substrate and passivation, which you need to get under control.

The in/out ports needs analog elements for impedance matching and protection, often consisting of variants of those transistors so glibly described as "binary" (digital). It there is anything that needs more element and circuit modeling than digital devices, it is of course the dark art of analog devices.

Finally, as no one can design the unique failure modes of new technology or devices, you have to put them to accelerated aging and testing to get to these initially unknown processes activation energies and thus the devices margins and statistical lifetimes. I guess the analogy in medical studies would be to look for side effects in data from final tests (and later use).

I take L-tyrosine and CoQ-10 for my bipolar disorder, as well as other supplements, and find them very helpful. Some study show these help Parkinson's patients since it is a dopamine related illness, too.

It's good to investigate what you are doing with your nutrition rather than just blaming science for not coming up with a cure. There's a genetic component to bipolar, too, but by being careful about what I eat and educating myself about nutrition, I do a lot better than if I just said oh well, science doesn't have a cure. Perhaps he could devote some time and effort to working on improving the American diet and getting the garbage out of our food supply.

Perhaps Grove ought to consult a nutritionist instead of just bitching - or use the Internet to do some research on what supplements have proved helpful for his illness.

Everybody who thinks modern out-of-order microprocessors are simple should watch
http://stanford-online.stanford.edu/courses/ee380/040218-ee380-100.asx

But circuits nowaways - may be on par with Mother Nature.

I'm late, but I think this deserves yet another "Ah, no."

I am a chemist in a company that is run by engineers. We routinely have discussions about why we can't just pull a new material out of thin air the way our EEs design a circuit.

There are two schools of thought that I encounter- that scientists are wooly-headed and undisciplined, and would be far better off if they would take a more engineering approach to science (this sounds kind of like what Grove said). This is usually something I encounter in engineers that have no experience with chemistry.

The other school that scientists are wizards, and that our work is far beyond what anyone can describe rationally. Chemistry is a subset of Black Magic, and is capricious and untrustworthy, though indispensable. This is no less frustrating, though, because there is the sense that the science is too inchoate to be relevant, and tehy are looking for me to furnish them with a black box that will provide them with some result, and they would rather not have to worry about the details.

What I want to know is where my holographic storage discs are. They have been working on them since the 1960's, about the time L-dopa was first used in Parkinson's, and they still haven't been released commercially. On the other hand DNA microarrays have only been around about 10 years but have now become one of the most powerful genetic research tools available and have found numerous practical applications outside the lab.

It is easy enough to pick out one particular subject in a field that has progressed rapidly and compare it to one particular subject in a different field that progressed slowly, but that is merely cherry-picking data to fit your existing conclusion. Those anecdotes do not provide any evidence that one field is inherently more productive than the other.

For those of you who suggest that Grove doesn't know what he is talking about, I highly recommend reading his 1996 article "Taking on Prostate Cancer." (http://www.phoenix5.org/articles/Fortune96Grove.html). The vigor, discipline, thoroughness, determination and intelligence with which he approached the problem of deciding what treatment to utilize are - to me - awe inspiring.

Second, for those of you who suggest that Grove is an idiot, I feel compelled to state the obvious. The absurdity of the assumption that he is unaware of the differing levels of complexity between chips and cells speaks more to conceit of the speaker than to any aspect of the reality of Andy Grove.

Third, how do any of you know what he does or doesn't do with his money?

Fourth, it is all too easy to dismiss what anyone with an incurable disease has to say by slapping the desperation label on them. There but for the grace of god, genetics, random chance or what have you, go I, might be a helpful thought to keep in mind when that temptation rears its ugly head.

Fifth, did he really suggest that medical research should be moving at exactly the same pace as the chip industry (i have not heard this speech)? i would think it more likely that he suggested, albeit forcefully, that the field of medical research could learn a thing or two from the chip industry.

Take complacency, for example. With respect to levodopa, I have heard multiple scientists say that its introduction unequivocally caused a major slowdown in Parkinson's research - because folks were so wow'd by its benefits they thought "excellent, we're done," but as anyone who has seen what that drug does to people when the honeymoon period is over will know, they were, and are, so not done - complacency, not just complexity, has played a major role in the lack of progress in Parkinson's research.

And while you can be sure that any company falling victim to complacency in the chip market would surely have meant failure, 40 years down the line, the Parkinson's disease research field is alive and well, putting food on table and kids through college, while people with Parkinson's continue to struggle through an average of 18 years with this disease on a drug whose useful life generally peters out at about five years.

Certainly, it is a question of complexity, but it is also a question of priorities and urgency.

i would like to clarify. when i say major slowdown, what i mean is that much of the research moved away from trying to find a new, improved therapy and instead focused on trying to fix levodopa's problems - an endeavor that has yet to succeed.

Octopussy, when chips have: the information storage capacity and density of a genome; On board individual scalable fuel cells; Multiple long and short range communication protocols; are on the fly reconfigurable according to self sensed need and make faithfull copies of themselves call me. Then we can begin to talk neuroscience and massively parallel analog systems.

In the meantime expect the chip plants to be bombed by greenies who raise the spectre of 'grey goo' spreading across the planet. If you think the stushie over Venter's misdescribed 'synthetic biology' wasn't hysterical....

Classic Post!lol!

@39: String theory is a sub discipline of physics (actually a sub discipline of a sub discipline) while dark matter is one aspect of cosmology. No one dismisses the entire discipline of physics because of these two.

Meanwhile the entire science of climatology and the researcher's competence is regularly called into question by self-righteous wankers and dick-headed religious types try to destroy biology in anyway they can.

Really there is just no comparison.

Another difference between biotech/pharma and the computer industry seems to found in the area of openness vs patenting and knowledge lock-in; more open source in the computer industry, more lawyers and fine-print patent stuff in drug design. Does that affect innovation?

Grove's statement was stupid, but no more so than a lot of the microelectronics-bashing on this thread.

A transistor is anything but simple, and we certainly don't have a complete understanding of them. Saying that it's just a straightforward on/off switch is nonsense.

A transistor (like all electronic components) is an analog device. The creation of digital circuits involves overcoming the transistor's nature, rather than exploiting it. On a very crude level, everything may be a matter of one and zero, but unambiguously defining one and zero in a complex, noisy, nonlinear, rapidly changing system isn't exactly straightforward. When you have nano-scale components running at over a billion cycles per second, a vast number of physical effects start to screw you over, and overcoming them is a major feat of engineering.

When you link transistors, things get even worse. You may want one transistor to control another, but in practice the interaction will always be two-way. Furthermore, a transistor will always interact with its near neighbours, regardless of whether you want them to or not. Getting data to flow the way you want it to (without the transistors doing something else entirely) is another major feat of engineering.

Once you are up to the level of ones and zeros, things still aren't that simple. Designing a four-bit ALU with a handful of simple instructions will have your head spinning. Scaling that up to a 64-bit floating point unit with a large instruction set is something else entirely.

I can't comment on the specifics of what Grove said, though I do agree that complaining that we haven't cured Parkinson's is pretty much the same as my continuing complaint about the lack of usable jet packs and voice recognition and personal hovercrafts and transporters ala star trek. Really, didn't you think we'd have those by now? Yeah, it's cool that my laptop runs way faster than the super-machines of the past, and that I can see things that are happening across the world, but I really really wanted a jet pack. And, admittedly, we can't fly (though birds & bees can, with their teeny little brains, that we don't understand at all). But, we can recognize words, effortlessly, magically, compared to the poor performance of your average voice recognition machine. And, to cite a subject even dearer to my own heart, I continue to be amazed at the abysmal performance of excellent pattern recognition software. These are simple problems for our brain, compared to the complexity of the processing that fails in Parkinson's.

But, in spite of this Grove's talk was part of the new "science & society" series at SFN, and it's extremely important that we listen to folks like him (and Christopher Reeves, when he was alive), and Jim Moran, and Mike Wallace. Yes, they say things that we think are stupid sometimes, but we need to know that, so we can figure out how to talk about what we do effectively.

We also need to understand the enormous need of people who are personally suffering from disease. Yes, Reeves & Grove are irrational in thinking that when they jump in, magical cures will appear to age old diseases, that scientists simply weren't motivated enough before. But, of course they are irrational; they are suffering and dying.

Looks like a lot of the people whining about IT being picked on in the comments, either haven't read all the comments or are ignoring the ones that shoot great big holes in the "IT is as complex as biology" concept.

For starters, please see comments #48 and #52.

When microchips can do everything described in #52, then we can talk about how IT might -- MIGHT -- approach biological complexity.

One lives, one learns.

The great PZ is not above the odd bit of pettiness, eh? From the evidence above, the allegedly rational crowd here isn't above the odd bit of pointless comparisons of phallic dimension either.

If you heard a chorus of chuckles, that'd be the smarter ones in the ID crowd enjoying the irony of an obviously designed system being compared with one for which we strenuously (and correctly) deny design.

a-nony-mouse wrote;

...complacency, not just complexity, has played a major role in the lack of progress in Parkinson's research.

That doesn't ring true; the barrier to finding more effective treatments for Parkinson's has largely been due to the lack of fundamental understanding of the disease process, along with the complex pathology of the condition.

Any treatment with neurotransmitter agonists is likely to have a short lifespan of efficacy, simply due to normal neurophysiological processes, coupled with the fact that such regimes address symptoms of the disease not the underlying pathology. This has been know for a very long time, and none of the Parkinson's researchers I know felt that would be out of a job any time soon, simply because L-dopa became available. (Although, I'm fairly sure they'd - to a man and woman - rather be unemployed.)

The fact is that the disease process is still being elucidated, even though there has been much research into the roles of the major pathological elements and gross neurological changes. It is now becoming clear that some of the major diagnostic features of the disease, such as Lewy bodies may not be as important to the primary disease process as might be expected. This kind of insight is largely due to molecular cell biology, and is therefore inherently linked to the progress being made in that field.

Human molecular cellular biology is really a field which has only come of age in the past couple of decades or so, and the emergence of new technologies in the past decade have allowed unprecedented progress in understanding how complex pathologies can result from fundamental molecular reactions.

It is one thing to look at a brain and see that neurons are being depleted from the substania nigra, or even to measure increases in alpha-synuclein levels, but the tools simply have not been available before now to investigate how those observations might be linked. Even the normal behaviour of synucleins is only just beginning to be understood; the biochemistry, genetics, subcellular localization, and intracellular processing the proteins can only be properly understood using recently available tools.

This bit is particularly offensive, by the way;

And while you can be sure that any company falling victim to complacency in the chip market would surely have meant failure, 40 years down the line, the Parkinson's disease research field is alive and well, putting food on table and kids through college, while people with Parkinson's continue to struggle through an average of 18 years with this disease on a drug whose useful life generally peters out at about five years.

What, Parkinson's researchers and their families are immune to the disease? Their rich diet of folding-money, champagne, cocaine, and self-satisfied egotism prevents them from becoming ill?

They probably only went into research science for the money, sex, and adoration by layfolk?

when i say major slowdown, what i mean is that much of the research moved away from trying to find a new, improved therapy and instead focused on trying to fix levodopa's problems

Did it? Or was it simply that those with the expertise to develop Parkinson's treatments have tried to modify the existing treatment regimes to improve their efficacy and lifespan, whilst also seeking new and novel treatments? (The latter being limited by the pace of progress being made by those studying the disease.)

- an endeavor that has yet to succeed.

Along with all of the other things that haven't been done yet, but which I can imagine happening. Wishful thinking doesn't save the world.

With all of the money in AIDS and Cancer research, where is the Panacea?

Why isn't there a cure for the common cold?

@a-nony-mouse (#50 & 51):

I don't think Grove is an idiot. His accomplishments in the chip business make it clear that he is not. However, some of the things he said are most certainly idiotic.

Regarding PD research, it's easy to complain today that too much effort went to trying to improve levodopa. But imagine the situation at the time. You have a new drug that does wonders for PD, at least compared to all previous treatments, but that drug isn't perfect.

How to do better? You can try to improve a (relatively) good drug, where you can at least imagine that optimizing the chemistry, dosing, PK, etc. might make it much better, and relatively quickly. Or, you can go back to the drawing board and try to find something totally new, where history shows that success may take decades.

Is it any wonder that many researchers picked the first approach? More importantly, do you think their decision was clearly wrong at the time? Personally, I don't think it was wrong at all, and certainly not wrong in light of what was then known.

I'll also point out that trying to improve levodopa was the right choice according to Grove! After all, one of his big complaints was that pharma execs need a stronger drive to bring products to market. That's exactly what the effort to improve levodopa was - an effort to bring new and better products to market. Quickly.

And it worked. Today, we have levodopa + carbidopa (Stalevo), which is a much better product. Nobody prescribes levodopa alone any more.

In the meantime, research on more fundamental treatments that might "cure" PD, such as fetal tissue transplants and deep brain stimulation, haven't yielded much in the way of new products. Yes, DBS is marketed, but there are lots of problems with it, so it's generally reserved for patients with the worst cases.

I think the PD field nicely illustrates that complacency about bringing products to market is not the problem at all. If anything, the opposite is true. The drive to bring new products to market, regardless of their absolute benefit may be part of the problem.

Ray Kurtzweil wrote an entire book on this very premise: "computing power is doubling about every 2 years, therefore in 20 years we should all be immortal." It's possibly the dumbest idea I've ever heard.

Andy is ahead of you all. He's got you all quacking - now to get you quacking about the right issues.

IT's not the analogy. It's about competency, feeling the urgency of the person who is ill. And if any of you don't think of GDNF in the paragraph in Newsweek [which some of you admittedly didn't "finish,"] that talks about a drug being "wrongly convicted and benefits lost forever", you shouldn't be posting about Parkinson's at all.

Who cares about how drug development compares or doesn't compare to a chip. Good work Andy!

"Ray Kurtzweil wrote an entire book on this very premise: "computing power is doubling about every 2 years, therefore in 20 years we should all be immortal." It's possibly the dumbest idea I've ever heard."

That's what is called the "geek Rapture". Instead of being raptured up to jeebus, we'll all be raptured up into cyberspace.

apdpatient wrote;

Andy is ahead of you all. He's got you all quacking - now to get you quacking about the right issues...It's about competency, feeling the urgency of the person who is ill...

No ammount of businessman's rhetoric, wishful thinking, or empathy is going to make drug discovery or biological research quicker.

Grove is simply very wrong in his assessment of how pharmaceutical research is driven, and especially so in the case of Parkinson's. The fundamentals have to come first. Does he really think that the pharamacueticals industry is afraid of setting targets to make money? The idea that pharmaceutical companies reject potential drug compounds on the basis of uninterrogated data from clinical trials is an absolute nonsense, for instance. Even the idea that putative drug compounds are rejected completely and without refinement is not true.

The sad fact of any serious disease is that many people will be affected and harmed before prophylactics, treatments, and cures become available. The only way to make the process of drug discovery faster for any given condition is to commit more resources to that single project, but we live in a real world with finite numbers of scientists, amounts of money, time, etc. Who will decide whether your disease is more important than another, and whose suffering is the most tollerable that they can go without?

If there are real issues that can be addressed, then they perhaps lie in very parctical areas, such as, national and international funding, international and regional licensing , data sharing and collaboration, and so on. A lack of research into the rarest conditions is a serious concern for many people. But, if we are going to bring a business model such as is seen in the microprocessor industry, then it may be that such anti-competitive issues will remain.

A respectful reply, thank you. Knowing little about the micro chip, I can't really talk about that comparison and as a patient don't think it's the real point. I think he is talking about an attitude among other things, of commitment, championing the cause, getting it done. Why does it take a company three years to publish toxicity results? I am not naive about the drug development process. I know the sequence that's involved and how long it takes. But I also have developed a lack of trust in big pharma, because all we see are 'me too' drugs. Why do they not take more chances like the smaller companies are doing? They have more money. I understand the lack of models for PD, I understand the lack of targets and biomarkers. But when a drug performs well in clinical trials, when patients are on it for 3 years, with miraculous recoveries like going back to a personal architect business, NO ADVERSE EFFECTS, but written off as a placebo effect because it was a phase I unblinded trial - 3 year placebo?- one loses faith. How can you do that when cells are dying? You can't..to anyone with PD that's ridiculous. Changes are needed to restore our faith in pharma.....to us it just looks like bottom line over human suffering. Hopefully this doesn't happen too often! But you are really dealing with two issues here; i) Andy's analogy, which isn't very well received to say the least and ii)a very sensitive generation of advanced PD patients whose only hope was halted for unconfirmed and downright faulty reasons and a sloppy phase II trial with enough changes in the variables to make a sixth grade science fair winner drop his jaw. Enough reasons to split and upset the medical community, not just the patients. It was done callously,abruptly, with not an ounce of compassion or even direct notification. It's enough to make a person quack.

apdpatient, if you want a system where anecdotes trump statistics then you want 'alternative medicine' not the proper variety and you certainly don't want science. You also don't seem to realise that it is not the pharmaceutical companies' fault if the financial system is set up so that it is not worthwhile to develop a drug that will only 'work' for a minority of patients. A minority you have no way of picking from the majority.

That is also partly why we don't have personalised medicine yet, it simply doesn't make financial sense for a drug company to initiate studies that will decrease the number of patients that get prescribed their drugs.

BTW I do not, and have not ever worked for or in the pharmaceutical industry. There was one short period where I was on money the source of which I was not told but might have been drug company money. I was doing basic research embryology.

Peter Ashby

" if you want a system where anecdotes trump statistics then you want 'alternative medicine' not the proper variety and you certainly don't want science"

Are you saying that statistics trump patient observation? Are you saying that testing for PD on a scale is accurate no matter whay time of day? week? hour? That statistics can be very inaccurate? Are you aware of the fact that the internet has produced a community of chronically ill that realize that doctors are on the payroll of many drug companies, they don't really provide enough information or protection in the Informed consents? That they don't follow through with Informed Consents? That the IRBs are often irrelevant? That the sponsors have all the say and the investigators get all the blame? But when you are paid to take it.....well

I don't want alternative medicine i want alternative clinical trials with a Bill of Rights for trial participants. I want integrity returned to medicine including the FDA, and I want competence back as the first priority before handing out certifications. I want doctors and patients to COMMUNICATE and doctors to realize they simply are not superior in knowledge anymore.

Thanks for declaring possible pharma money. IT's not tHe money; we need pharma money. It's the integrity of the medical research and drug industry and the trust of patients that they will do the right thing that required you to even think of listing a possible conflict of interest. Drug money is good when the behavior of those who recieve it is PATIENT CENTERED.

Finally,
"You also don't seem to realise that it is not the pharmaceutical companies' fault if the financial system is set up so that it is not worthwhile to develop a drug that will only 'work' for a minority of patients. A minority you have no way of picking from the majority."

I've had young onset PD for 20 years. Who do you think realizes that more between the two of us? That doesn't make it right.

How many people make it worth it to save them?

Whatever is stated above, apdpatient does know what she is talking about.

apdpatient said, "Are you aware of the fact that the internet has produced a community of chronically ill that realize that doctors are on the payroll of many drug companies, they don't really provide enough information or protection in the Informed consents?" This is an accurate statement.

I certainly hope, Mr. Ashby, that you are not of the group of people who feel that patients "belong in their place."

You said, "You also don't seem to realise that it is not the pharmaceutical companies' fault if the financial system is set up so that it is not worthwhile to develop a drug that will only 'work' for a minority of patients. A minority you have no way of picking from the majority." So you feel that it should be okay for pharmas to develop only for the majority; e.g. cancer. And that the small...1 million American's with PD...are in the minority and should realize that groups like cancer should have first "dibs" at cures!! WRONG!

We...the educated PD community...know that pharma is about money. It is about how much money can the company make. We read the financials for these pharmas...we are not iliterate to the facts. Case in point...you said, "That is also partly why we don't have personalised medicine yet, it simply doesn't make financial sense for a drug company to initiate studies that will decrease the number of patients that get prescribed their drugs."

It is also about patents, who gets it and doens't get it. Look at the patent for one promising trial that is being held hostage by a big pharma company. There are big and small phamas out there that would take over the patent, but for whatever reason the big pharma company won't release the patent to another. apdpatient said, "But when a drug performs well in clinical trials, when patients are on it for 3 years, with miraculous recoveries like going back to a personal architect business, NO ADVERSE EFFECTS, but written off as a placebo effect because it was a phase I unblinded trial - 3 year placebo?- one loses faith." This single trial that apdpatient talks about caused the majority of us to lose faith in big pharma.

So, when a trial came along that was similar to the trial that was halted after 3-years, I joined it. Mr. Ashby, how many clincial trials as a healthy or an ill patient have you been involved with?? If you were a terminally ill patient, as we all are (19 yrs for me), would you allow a surgery to preform brain surgery on you as you crossed your fingers you would not have a harmful effect from the therapy being insered deep into your brain. That is how desperate we are for a therapy that does not have horrible side effects...and works....or better yet, is a cure.

We also want patients to be treated as equals in the trial process..."PATIENT CENTERED." Yes, how many people makes it worth the effort.

We all want, "...alternative clinical trials with a Bill of Rights for trial participants. I want integrity returned to medicine including the FDA, and I want competence back as the first priority before handing out certifications. I want doctors and patients to COMMUNICATE and doctors to realize they simply are not superior in knowledge anymore."

stitcher and apdpatient, calm down and stop kneejerk reacting to what you think I'm saying instead of what I am actually saying.

I am for eg NOT denigrating the experience of individual patients. But you cannot do science with an n=1, or a self selected community. You are also ignoring things like placebo effects and remission (and NO I am NOT implying anyone actually reacted to this and not the wonder drug). That is why we run trials and why you need stats to tell you if there was an effect. That some people were apparently helped does not trump the statistical analysis (and I am not talking about any particular trial, this is an important principle).

What you seem to be asking for is the right of patients to decide on their own that the trial has worked and now give me the drug, regardless. I could introduce you to arthritis riddled people who thought Vioxx was the best painkiller they have ever taken and they have no heart risks so why can't they take it? Money again, the pharma cannot risk the lawsuits and has no way to tell who can safely take it.

And for the record I am a matched control for a large population based pharmacogenetic study into type II diabetes risk. The needle seems to have gone through the vein and my lower arm filled with blood. I also took part in a number of studies during my PhD in physiology, my breathing is apparently too hard to capture ;-) I have also spent a weekend shut in a Dutch Motor Inn brainstorming ways to cure muscular dystrophies, unpaid. So I have more than done my bit for biomedical research.

And for the record life is a terminal illness if survival for 19years counts. Lets not get too hysterical.

The pharmaceutical industry has a long history of acting as exactly that - an industry. The only way to raise the vast revenues required to develop drugs is to seek capital via the existing mechanisms of commerce, to market drugs competitively, and to supply the greatest demands. They are - broadly speaking - doing nothing wrong, not even morally wrong in that. The vast majority of society puts self-interest first, and would rather be economically secure than a poor philanthropist; the industry exists within that broader context.

In many respects, we've ended up with the pharamceutical industry we deserve, because we've all voted for various governments (in my case, in the UK) that have fostered and regulated a business model which sees the pharamceuticals industry as, well, businesses.

I think that there is good reason to think that the industry is changing for the better, looking for instance at the recent changes in anti-retroviral drug supplies to the poorest nations would suggest that the industry is developing a conscience. There is much more of drive to develop drugs which are effective for small- and sub- populations of patients, and this is particularly the case in the development of new cancer treatments.

So you feel that it should be okay for pharmas to develop only for the majority; e.g. cancer.

Except that cancer is not a single disease, and it is becoming more and more obvious that future treatments will need to recognise that almost every tumour is different, and will respond differently to treatment. Cancer may be recognised by the majority as a single condition, and this may give rise to better consciousness, better support networks, and possibly more lobbbying power, but the majority is mistaken.

I think it would be very sad to think that cancer is over-researced at the cost of other conditions such as Parkinson's, but I don't believe that to be the case (especially not if you consider "cancer" to be an umbrella term for thousands of individual conditions). The same argument could be made that Parkinson's, which is probably the most researched neurological disorder, is given undue prominance over other conditions, simply because of its prevelance and seriousness. Well, the sad fact is that priorities have to be decided.

That is how desperate we are for a therapy that does not have horrible side effects...and works....or better yet, is a cure.

Of course, and I think that most people can understand that, because I think that most adults have some experience of terminal illness.

Unfortunately, there is still very little way of rushing progress. There are certainly improvements which could be made in the research process, but many of them really need to come from government and regulators, for instance to incentivize data sharing and the release of negative trial data and toxicity results. This kind of co-operation is never going to happen whilst the pharamceutical industry is run and regulated as essentially a free-market.

Any company that risks financial ruin by breaking with conventional practice, not only stands to lose the money of its investors, but also will not exist to develop any new therapies.

If industry finds itself unable to change, then government has to take the lead.

Well said Bernard Bumner. I think people should also learn a bit of history, they forget that syphilus was once as bad as AIDS before the antiretrovirals. Being HIV positive in the West today is no longer to have a terminal illness as most people understand it. They have many decades of life ahead of them. This is so much the case now that the young are not taking it seriously enough and infection rates are rising again.

That is just one example. Taking one problem area and declaring that because it hasn't been solved means the industry is completely broken or immoral ignores serious facts. The problems we have left are still there because we have done the easy ones. The Nobel for oral rehydration fluid has already been won, now the question is what flavour would you like?

It would be wonderful if there were no more disease wouldn't it? except experience tells us that the longer life that would bring would simply allow other diseases/conditions to flourish. There is an epidemic of PD and Alzheimer's largely because people are living longer. This means there will always need to be biomedical scientists, pharmaceutical companies and patients. Railing at one of those by one of the others is unhelpful and counterproductive.

Peter Ashby,

You didn't answer my questions, grouped the two patients together and did a bang up job of demonstrating the patronizing attitude of the medical community. Hysterics and knee-jerk reactions? Any knee jerk I may be guilty of comes from dyskinesia.

apdpatient, I wouldn't want to be patronizing to you or put words in the mouth of others, but I would hope that what Peter Ashby means is that we - collectively - need to somewhat dispassionate and detached in considering these issues.

With respect, you have a very subjective perspective, a bias developed from personal experience which - unless you are superhuman - will override much of the objective analysis, if it contradicts your own observations. So, in matters of policy , we do need to be very careful in deciding how much weight to give to the views of patients, carers, and sufferers, and give deference to professional experts.

All of that is cold comfort for anybody suffering from a particular illness or disease, of course.

I think that there is a very valid argument to say that the medical profession has been guilty of promoting the idea that diseases can and will be cured, and that treatment is everything. In the process, I think that palliative care is often neglected, and people aren't helped to cope with their illness. I'm not suggesting that hopes and expectations of cures should be discouraged, but I do think that many people - especially ill, desperate people - have unrealistic expectations of medical science.

So, in my opinion, one thing that needs to happen is that people should be given better help to cope with the psychological ramifications of their illnesses. Part of that process would be to convince them, or rather, demonstrate to them that their illness is being taken seriously. Clearly, that must involve honest and transparent communication between parties like pharmaceutical companies and patients groups.

However, such a process needs to be tempered with realism, as well as ambition. It is in that respect that Grove - which is where this all started - was misguided. Nobody should dismiss the concerns of patients, but equally, patients need to be able to place trust in the professionals.

I recognise that - especially when it is your life on the line - appeals for rationality and objectivity can seem uncompassionate and patronizing, but assessing one's own ability to consider a situation without bias is very difficult.

I think he is talking about an attitude among other things, of commitment, championing the cause, getting it done. Why does it take a company three years to publish toxicity results?

Ah, then Grove might be comparing drug tests with testing of new semiconductor processes or designs. They are run in a staggered fashion to compress the project time as much as possible, by taking information from the first test to modify the later.

AFAIU we can't do much of that in tests on humans for moral reasons, even or perhaps especially if patients are willing to do so. (But this is a contentious issue, for sure.) And I think the last rounds is targeted to expand on statistics, especially on side effects, another bow to morals (and perhaps economy as well, again contentious).

If he is considering the work leading up to human tests, I'm quite sure it is done, why shouldn't it be?

And then I doubt he is complaining about the late (and for all I know perhaps incomplete) use of evidence-based medicine. It is an excellent way of getting it done, in a timely fashion.

With respect, you have a very subjective perspective, a bias developed from personal experience which - unless you are superhuman - will override much of the objective analysis, if it contradicts your own observations. So, in matters of policy , we do need to be very careful in deciding how much weight to give to the views of patients, carers, and sufferers, and give deference to professional experts.

So you want to shut up patient groups and take them out of the policy process? Good luck.

Such a technocratic principle might sound like a good idea to you, but is today's society built like that? No.

It is a social fact that organized interest groups by using the media, lobbying politicians and doing politics in other ways, can not be disregarded.

You will have to live with the fact that not only the "professional experts" you hold in such high esteem have a saying, but that media appearances by Michael J. Fox, for example, will affect the policy process.

I appreciate the respectful replies. It's a little unfair, now that the conversation is at this point, to not let you know that I am [and I think I can speak for stitcher as well] talking about a specific incident that has rocked the PD community. Andy Grove is referring to it in the section where he talks about treatments that are "wrongly convicted". Hopefully it doesn't happen too often, but it opened our eyes as very involved activists. I do understand the issues you speak of - the need for objectivity, being dispassionate, the importance of quality of life care, etc.

I don't claim to know biochemistry, but I'm willing to bet that the Internet culture that has developed in the last ten years is creating a new paradigm. We are up to date on specific research; after all, we had to give up our careers and have much time on our hands. We are not elderly.

I know stitcher personally. Stitcher is in the cere 120 gene therapy trial.

And we are doing right now what we think will end up in that new paradigm - COMMUNICATING.

http://pdpipeline.org

It includes a database of treatments in development including pre clinical research.

Qetzal, I am a little late but would like to say the following in response to your comment that all the levodopa-centric research had "worked.* First, the term levodopa is commonly used as short hand for carbidopa levodopa (the combo has been the standard of treatment since 1975, when it was introduced).

Second, here is a taste of what they knew back then about the wonder drug, levodopa - date, 1980:

The progress of 178 patients with Parkinson's disease who began treatment with levodopa between November 1969 and December 1972 is reviewed after six years. [125] patients showed an initial improvement...exceeding 25%, ...By 1978 only five patients had maintained their initial improvement... Involuntary movements were the commonest complication of treatment.... Peak dose dyskinesias, ... affected 80% of patients. .... Involuntary movements increased in frequency and severity as treatment continued. End-of-dose deterioration...occurred in 65% of patients: ... Psychiatric side effects included toxic confusional states, visual pseudohallucinations and paranoid psychoses ... After six years of treatment with levodopa, 32% of the patients had unequivocal dementia.
(Q J Med. 1980;49(195):283-93. The impact of treatment with levodopa on Parkinson's disease. Shaw KM, Lees AJ, Stern GM)

Third, there has been almost zero progress in 40 years of trying to fix levodopa - I will summarize for you:

The transition from levodopa (1970) to Sinemet (levodopa/carbidopa, 1975) resulted in a 52% reduction in the incidence of nausea/vomiting, a 60% increase in the incidence of dyskinesias (involuntary movements), and had no impact on wearing off or on/off fluctuations.

The transition from Sinemet to Sinemet CR (controlled release, 1991) resulted in no improvement in on/off fluctuations, a reduction in the frequency of dosing per day, and a 35% increase in the incidence of dyskinesias.

The transition from Sinemet CR to Stalevo (levodopa/carbidopa/entacapone, 2003) resulted in - if you average the numbers from each of the clinical trials listed in the package insert - about 51 additional minutes of on time per day. It also resulted in a 75% higher incidence of dyskinesias, and that was only after six months.

So for the super duper summary, after 40 years of effort and untold amounts of money spent trying to fix levodopa, the only real improvements that have been achieved are:
* a halving of the incidence of nausea/vomiting
* a reduction in the number of times one has to take medication every day
* and less than an hour of additional on time per day

And a four-fold increase in the incidence of dyskinesias.

I am not impressed.

Source: http://anukets-crusade.blogspot.com/2006/08/levodopa-if-this-is-gold-st…

Bernard:
"With respect, you have a very subjective perspective, a bias developed from personal experience which - unless you are superhuman - will override much of the objective analysis, if it contradicts your own observations. So, in matters of policy , we do need to be very careful in deciding how much weight to give to the views of patients, carers, and sufferers, and give deference to professional experts."

Gustav:
"So you want to shut up patient groups and take them out of the policy process? Good luck."

Nothing that Bernard writes can be construed as saying that unless you have on some very weird spectacles. This discussion is hard enough without people failing to read what people have actually written instead of seeing what they expect to see.

You go from being careful in deciding how much weight to shutting up. Nothing in there says patients should shut up, only that there are dangers in listening uncritically to all groups or everything they say. For eg I detect a failure to differentiate several separate issues: care, which is a medical issue; trials, which are a problem both for pharma AND bodies like the FDA (not all trials are in the US); basic research, much of which is not done by or funded by pharma. Much of that is funded by patient groups and I see problems there. Not all researchers are ethical and honest when it comes to grabbing research dollars from desperate people, I have some experience of this.

Failure to differentiate these issues (oh and the funding systems) means we are talking past each other.

Yes, I agree, it is important to read carefully and, yes, he didn't say "shut up", he said "give deference to professional experts." Still, that sounds rather technocratic, doesn't it?

I just observe that in today's world, we will have to live with the fact that patient groups and other kinds of organized citizens sometimes play a role in the policy process. Whether non-expert influence on the policy process is a good thing or not will have to be decided from case to case.

I was recently talking to someone who heads a large lab that attracts both biologists and engineers. Invariably, the biologists when they need help from engineers go and ask humbly.

Engineers, on the other hand, arrive at the lab and can't understand why biologists haven't been competent enough to answer all these questions. When they are presented with a postdoc grant for three years to work on a project in say, embryology, they take one look and wonder what they're going to do for the other 2 years and 10 months. Two years in, they usually have a much better respect for biology and basic research in general.

A better question: Why was Newt Gingrich speaking at SfN?

And best lecture of the conference goes to a non-neuroscientist: Susan Lindquist.

But this is what everyone missed out on.

READ Andy Grove's speech to the Society for Neuroscience in its entirety

See What's New
Click on "READ Andy Grove's speech to the Society for Neuroscience in its entirety"

www.pdpipeline.org

to bernard bumner

you said:
"such regimes address symptoms of the disease not the underlying pathology."

I trust you are stating the obvious intentionally rather than in the hope of educating me. Yes, I am aware that there is neither a cure nor a disease modifying therapy out there as yet.

Perhaps I should revise my assertion and say that the advent of ldopa rerouted significant energy/funding from developing a symptomatic therapy into basic science and trying to fix levodopa.

Regarding complacency,

you said:
"That doesn't ring true; the barrier to finding more effective treatments for Parkinson's has largely been due to the lack of fundamental understanding of the disease process, along with the complex pathology of the condition."

The evidence on which I base my assertion that this lack of progress (defined, in this case, as the failure to either improve upon levodopa or develop a superior alternative) stems in part from complacency is as follows:

Given what was known about levodopa's "long-term" effects pretty much from the beginning (if you are unfamiliar with levodopa, see my post #78 on this thread), the research community's adherence to the idea, from a public relations standpoint, at least, that levodopa is a good drug, is telling. By public relations I mean that if all one reads are texts written for patient consumption, including the package insert, one comes away with a much less complete understanding of what is really in store than if one reads actual research articles and studies.

An example - I googled "side effects of levodopa," and here is a summary of the first hit, medicinenet.com (health and medical information produced by doctors):

First of all, it says the side effects are usually reversible, which is odd because a) aren't most side effects reversible (and the 3 other drugs I checked didn't say that), and b) almost no one ever goes off levodopa, which is presumably one major method for reversal.

Second, while it categorizes dyskinesia as common, serious, and possibly responsive to dose reduction, it describes them as occasional. It lists potential psychiatric disturbances, and gastrointestinal side effects (characterized as common) piece o' cake, right?

Now take a look at the summary below of a description of what one can expect from "long-term" (defined as 2-5 years, with average length of time one lives with the disease being 18 years)

The initial "levodopa honeymoon" during which the med actually works lasts 2-5 years in most patients. However, eventually, "the patient will lapse into the final and irreversible stage ...with complex motor complications that are extremely hard to tame." The authors term this period "paradise lost."

In this final stage "The daily performance of the patient is now dominated by swings between various "off" [med not working] and "on" [med working] phases and response pattern may become completely chaotic and out of control. ..."on" periods are almost invariably associated with dyskinesias [involuntary movements], which may, at this stage, be particularly violent and incapacitating. ... in many patients, the therapeutic window between pure clinical relief and dyskinesia exerted by a single levodopa dose becomes very narrow or non-existent, so that when a dose successfully turns them on, they will have obligatory dyskinesias... In many older patients, penalty for success of levodopa in alleviating the motor symptoms is the exacerbation of parkinsonian psychosis manifested mainly by visual hallucinations, paranoid delusions and confusion."
(Movement Disorders. Vol. 22, Suppl 17, 2007, pp. S379-S384. Management of Motor Complications in Advanced Parkinson's Disease. Melamed E. et al)

Now, you tell me - what is it that allows the medical establishment to be fully aware of a drugs humongous deficits and yet be party to the minimization of these deficits as presented to the people to whom it is prescribing the drug?

Do you think that if every PD neurologist and neuroscientist had to face the inevitable adverse, and, practically speaking, irreversible, effects of this drug, that they would have embraced the moniker "the gold standard," like they have?

Do you think that levodopa's short comings would be successfully being subsumed into the disease, in that dyskinesias are being listed as a symptom more and more frequently, and the effects of long-term levodopa therapy are routinely referred to as elements of advanced PD (see title of article quoted above), if every researcher knew s/he was going to have to experience them?

Do you think the attitude that dyskinesias are expected, as one neuroscientist said to me, would ever gain traction?

Do you think there would be even the slightest debate as to whether or not dyskinesias represented a toxic reaction to levodopa, if all involved in the debate were actually dyskinetic?
'
The answers, for me, at least, are clearly no, and it is complacency born of *not* having to face any of these eventualities personally that has allowed each of the scenarios I mention to become reality.

And regarding the offensive bit, point taken. It was poorly phrased. What I meant to convey was the fact that by and large, people researching PD do not actually have PD, and therefore their priorities are different from those of many people with PD, and, in all likelihood, they do not feel the same urgency that someone with PD might - it is just reality - I apologize for wording it so poorly.

The fact that Grove is an idiot does not automatically make microprocessors simple.

True. While PZ identifies Grove's major mistake (biologists haven't nearly as much freedom of modifying the system), semiconductor manufacturing is far from simple.

Take for example Intel, which AFAIU currently works by a "tick-tock" model.

Every other year they introduce a completely new process, which may encompass anything from increasing wafer size, retooling or building a new plant, managing new lithographic processes, new and/or purer materials, and nowadays often completely remodeled and non-linear (as regards leak currents) devices and processes. As hundreds of development people work inside Intel and many more outside on standards, processes, devices, equipment, et cetera for 2 years, that would mean hundreds of man-years. The manufacturing process is fiendishly complicated, with hundreds of steps.

And every other year they introduce new architectures, which again may mean anything from completely remodeling cores, memory handling, channels et cetera, to more minor changes. But never the less will mean going from lab work up to a couple of final chip production cycles, and again means many manyears.

I'm quite sure it may rival some large biomedical efforts. But of course Grove is naive if he compares with the necessary width of medical concerns, we aren't discussing one sickness here.

You have a transistor - a simple binary system (on or off).

If it only was that simple. Granted, of all possible transistor devices the industry will only use a few models. But as they shrink, these essentially non-linear devices needs to be understood anew, often with new materials, changed parasitic properties, new failure modes, et cetera.

Then you have other active (memory cells) and passive elements that couples through substrate and passivation, which you need to get under control.

The in/out ports needs analog elements for impedance matching and protection, often consisting of variants of those transistors so glibly described as "binary" (digital). It there is anything that needs more element and circuit modeling than digital devices, it is of course the dark art of analog devices.

Finally, as no one can design the unique failure modes of new technology or devices, you have to put them to accelerated aging and testing to get to these initially unknown processes activation energies and thus the devices margins and statistical lifetimes. I guess the analogy in medical studies would be to look for side effects in data from final tests (and later use).

I think he is talking about an attitude among other things, of commitment, championing the cause, getting it done. Why does it take a company three years to publish toxicity results?

Ah, then Grove might be comparing drug tests with testing of new semiconductor processes or designs. They are run in a staggered fashion to compress the project time as much as possible, by taking information from the first test to modify the later.

AFAIU we can't do much of that in tests on humans for moral reasons, even or perhaps especially if patients are willing to do so. (But this is a contentious issue, for sure.) And I think the last rounds is targeted to expand on statistics, especially on side effects, another bow to morals (and perhaps economy as well, again contentious).

If he is considering the work leading up to human tests, I'm quite sure it is done, why shouldn't it be?

And then I doubt he is complaining about the late (and for all I know perhaps incomplete) use of evidence-based medicine. It is an excellent way of getting it done, in a timely fashion.