Cannabis and post-truth legislation

A lot of reports these days are covering "fake news" -- stories without underlying truth, and there are cases where governments are making policies based on stories denying climate change and other similar unsupported ideas. I recently collaborated on a cannabis paper that I feel nicely encapsulates the challenges when voters and legislatures start to get involved in science.
My paper, written together with colleagues at Northwestern in this month's Movement Disorders Clinical Practice, is a timely report on a systematic survey of expert neurologists based on an idea by Danny Bega, an up-and-coming neurologist at Northwestern. When we surveyed expert neurologists about cannabis, everyone thought they knew what the appropriate uses of cannabis were but no two people thought the same thing. We think of the FDA as an approver of drugs, but in reality the FDA assesses the evidence for indications and dosage, and "approval" is really a determination that a drug is safe for humans and, when used in a defined set of individuals, provides a benefit to them that outweighs the risks.
In contrast, with cannabis, legislators are effectively simply "approving" its use, without the indications and dosing that any FDA-approved drug would come with.
Of course, cannabis is impossible to "approve" in an FDA process, because the the source plants are actually a family of plants, with dramatically different compositions including varying concentrations and ratios of cannabinoid receptor agonists (which cause euphoria and executive dysfunction) and antagonists (which cause neither). It would be like if the emergency department stocked generically "opioids," and some people presenting in pain got morphine, others got heroin, and another group got tea made from poppies.
Many people are aware of situations where legislators are attempting to legislate science, with people up in arms about policies denying global warming, evolution, risks of antibiotic resistance, pesticides used to fight zika that are neurotoxic to humans (and cause Parkinson's), etc. However, cannabis legalization represents the same mistake: policy being set using cherry-picked science.
In all these situations, people are attempting to set policy to reflect a perspective that exists in (at most) a subset of the opinions on the topic. There is a historical analog of this: throughout much of the 1990s, healthcare strategists attempted to encapsulate into medical guidelines treatment approaches identified through bringing together groups of experts to arrive at consensus on the best ways to treat a disease. These approaches failed miserably, resulting in another shift, this time to "evidence-based medicine." In the best "evidence-based" guidelines, experts on medical-scientific epistemology review all the papers published on a topic systematically, identifying conclusions that are broadly supported.
We need to ensure that when legislators consider science-based policies, that they take a lesson from medicine and adopt policies that appropriately reflect the best insight from across science, and then include a mechanism to review new developments. The importance of this point is encapsulated in the case-study of policies around the legalization of cannabis.

An Approval Process for Services

I am working on a telemedicine project and have been involved in telemedicine since 2004.  Telemedicine is obviously a solution to many aspects of care – people are admitted to the hospital for “observation” when, clearly, with sensors and video we could “observe” patients in their homes more efficiently and at dramatically lower cost, for example.  Telemedicine research is ongoing and is proving (sometimes for a second or third time) that telemedicine works.  The obvious question is, when do we consider telemedicine to be proven effective?  I realized recently that we finally have an answer to this question, and it’s in a partnership between Medicare and a group called the National Quality Forum.

For decades, the process of commercialization of a new drug has been well understood.  I’ve worked in both drug and device development and in each case, the process was clear and reasonably predictable.  The US Food andDrug Administration sets the rules for drug approval, and for the most part, it is straightforward.  When a lab discovers that some substance, a molecule or cocktail, has therapeutic potential, they can start to engage the FDA.  Typically, this involves first proving that the drug is safe for human use (after preliminary data suggests that the answer will be yes), then studying the drug in a series of progressively larger studies to demonstrate that it is effective.  Once researchers complete phase III – typically two large randomized, controlled, and blinded studies – the FDA gives its stamp of approval and the drug can be shipped to the pharmacy.

At this point, the drug is not just approved for use but there is also the expectation that it will be used.  If studies have shown that this drug is more effective that standard therapy, people may claim that to not use the drug constitutes harm.  If your doctor doesn’t offer you a prescription for a new, FDA-approved drug that has been demonstrated to be more effective than other options, you might be able to claim that you did not get good care.  If your insurance company didn’t cover it, you might complain to regulators.  Many doctors and patients want to use a new drug, even if the evidence that it is better than other options is ambiguous.  The FDA process isn’t perfect, but it is good enough that people are willing to invest in it.

In contrast, there are many models of care and therapeutic approaches that are known to be effective but, because they have no regulatory process, they never become the standard.  At the simplest level, a neurologist from the University of Pennsylvania has convincingly shown that referral to a neurologist for patients with Parkinson’s reduces hip fracture, nursing home placement, and mortality by about 20% each.  If there were a drug that did this, we would be shocked to hear a doctor didn’t offer it to his or her patients, but we readily accept that approximately half of Parkinson’s patients do not receive regular neurologist care.

There are other consequences, too: clinical research on drugs changes – often, decreasing dramatically – after FDA approval, freeing up funds to pursue the next breakthrough.  Once a model of care of mode of care delivery is demonstrated effective, the amount of research often increases, as other clinicians want more information and not to just rely on what they read in a scientific paper or heard at a conference.  In telemedicine, many bright academic pioneers have been slow to scale up, while entrepreneurs commercialize their innovations.  This happens for two reasons: first, without a regulator-established risk tolerance for approval, entrepreneurs and expert clinicians will have different perspectives on when a therapy is sufficiently established, and second, research dollars continue to be available even after the therapy is quite well established.

A relatively new organization offers us the chance to change this.  In the early 2000’s, largely driven by Medicare, there was a desire to promote the delivery of high quality care.  After some false starts working with professional societies, Medicare partnered with NQF to form the Measure Application Partnership, an initiative to identify pay-for-performance metrics.

In doing this, NQF developed a process to review and assess proposed measures of quality care, including process and outcome measures, and variously applicable to individual providers, to facilities, and to health systems.  With appropriate measures adopted, Individual providers might track whether they query about sleep disturbance in their Parkinson’s patients, facilities could measure inappropriate use of dopamine-blocking antipsychotics, and heath systems could track whether physical therapy referrals go to PT’s trained in LSVT-Big.

Although there are typically no restrictions against using a care delivery model without approval, there are good reasons to hope that NQF approval could simplify the process of getting a new model of care adopted.  This will be very important to healthcare in America as we recognize that the greatest challenge facing the American healthcare system is much less in the development of new treatments, and much more in access to the ones that currently exist.

There are good reasons to hope that the NQF could finally give us an FDA-like organization for approving health services.  I hope that we will see that not only will NQF approval create the expectation that a process or model of care can be made available, but also that, after NQF approval of a measure, research funding will move on to new questions (including a class of “post-approval” questions as with drugs) rather than continuing to support replication of prior studies.

Prion or not prion?

In 2009 at the World Federation of Neurology meeting in Miami - where long-time NPF leader Nathan Slewett was honored - Stanford Nobel Laureate Stan Pruisner publicly stated what prion scientists had been saying for a while: there was good reason to think that Parkinson's disease was a prion disease.

Prion diseases were discovered by Prusiner who was trying to understand the nature of a disease that seemed to cause symptoms in patients (well, mice and sheep) without any transfer of DNA.  Proteins in the body fold into shapes, and often the mechanical properties from the shape of a protein is more important than the chemical properties.  Proteins fold through a process called "chaperoning," where one protein helps another to fold in a certain way.  Prusiner figured out that sometimes a protein can fold in a way that causes other proteins to fold in the same way -- a sort of self chaperoning.  Prusiner called proteins that with this property (and a couple of others) prions.  In this situation, if you think about it, each time a prion chaperones the creation of another one, it adds another chaperone, increasing the rate that misfolded proteins are created.  If a particular folded form of a protein is damaging, this results in disease.

A number of prion diseases have been discovered. It is required to be shown that the disease can be spread through exposure to the misfolded protein.  It has been claimed that this has been demonstrated in Parkinson's with a mouse study widely reported and replicated.  However some recent findings have cast doubt on this finding - was the protein actually chaperoning alpha synuclein accumulation?

One of the alpha biologists of Parkinson's is Northwestern's Jim Surmeier. He is the guy who is in all the hard-core biology sessions at conferences and usually asks the first, hardest question.  A Udall Center director, Surmeier challenged the audience at the most recent Udall Centers meeting.  If alpha synuclein were a prion, it would be transmitted from cell to cell either by proximity, across the extracellular matrix, or across synapses, the cell to cell junctions in the brain.  It turns out that the centers of alpha synuclein pathology are neither adjacent nor linked by axons. (Scientists trace the neural network using the rabies virus, which very aggressively spreads up -- from dendrite to axon, the opposite of neural signaling -- neuronal connections.)

Drug users who took the mitochondrial toxin MPTP (instead of the synthetic heroin they thought they were taking) were found to have selectively poisoned their dopamine producing neurons. People exposed to Parkinson's-connected pesticides selectively lose dopamine neurons, even though these toxins are general mitochondrial toxins.  There's something special about dopamine neurons.

The way Parkinson's pathology spreads, it seems like if prions are part of the Parkinson's story, it's not all of the story.

The primary model for thinking about Parkinson's progression in the brain is called the Braak hypothesis.  Hideko Braak is a Finnish neuropathologist (i.e., a guy who cuts up brains) and he has created well known mental models like this one for both Alzheimer's and Parkinson's.  The Parkinson's model shows the disease starting in the brain stem and progressing into the forebrain, meaning it starts with the regulatory parts of the brain and progresses to the cognitive regions.

This model is wrong. It offers a nice framework to think about Parkinson's progression, but this framework leaves out key details and misleadingly suggests that the course of Parkinson's is fixed and inevitable. It's not. For example, work led by Daniel Weintraub at the University of Pennsylvania (at another NIH Udall Center) has shown that patients who experience cognitive impairment will progress on to dementia. However, work by Antonio Strafella at the University of Toronto - supported by a grant I managed - showed that patients who don't have cognitive impairment seem to have cognitive regions of their brains bypassed by the Parkinson's pathology - the disease jumps across or somehow skips those regions.

So, although we know that Parkinson's is linked to misfolded proteins, we also know that those proteins alone don't define the spread of the disease.  One of the first places Parkinson's hits is a region called the basal ganglia, which is a region rich in dopamine producing cells, and we know that throughout the disease, dopamine replacement is a central part of treatment.

At the Udall meeting, Surmeier asked us to consider that maybe dopamine neurons are selectively vulnerable in Parkinson's. Other neurons -- not to mention other cells in the body -- have alpha synuclein but they don't get Parkinson's.  They have mitochondria but are not killed by mitochondrial toxins. At least not at first.

The prion model and the idea that Parkinson's essentially diffuses through the brain seems to be overly simplistic. It's probably part of the puzzle, but selective vulnerability is another part.

The scoop on nilotinib

In a prior post, I told the story of how a genetic mutation provided insight that can help everyone with Parkinson's.  The story of nilotinib is an exciting development leveraging that same model. As with isradipine, inosine, and other studies, this is a case where a fundamental understanding of biology informed the development of a drug we hope can make a difference.

Back in 1998, a group of Japanese researchers first connected the gene for a protein they named parkin with juvenile-onset Parkinson's disease.  Parkin is one of the most important genes for Parkinson's, representing the most important recessive genetic cause of Parkinson's.  Recessive genetic disorders (i.e., both parents must be carriers) are interesting to scientists because they are situations where people get a disease because a cellular process doesn't happen.  Since DNA codes for proteins, and humans have two copies of each string of DNA -- one from each parent -- only when both copies of the code for a protein are damaged does the DNA not work at all.  When that protein is important for a biological process to work, if the body can't synthesize it, that process won't happen.

Patients with parkin-related Parkinson's provide us with unique insight into the disease.  With alpha synuclein, there are lots of ways it could be problematic. With parkin, we know we can look just at the cellular processes where the protein is necessary.

Parkin is a protein that attaches to things in cells to trigger the process of garbage collection -- cells contain tiny structures, lysosomes and proteosomes, that are involved in breaking up things in the cell that are not needed. Both lysosomes and proteosomes have been linked to Parkinson's disease. A scientist I've supported, Ted Fon, is studying parkin. His team has shown that parkin is linked to mitochondria -- the power plants in cells.  Recent research has suggested that alpha synuclein converges with parkin at the mitochondria.

Since alpha synuclein is the most important protein in Parkinson's and parkin is second, this convergence probably points to something important.

As these connections are found, there is increasing enthusiasm for the idea that we could stop Parkinson's at the cellular level by addressing this "garbage collection" problem.  A team led by a brilliant scientist at Johns Hopkins named Ted Dawson figured out that a cellular chemical called c-Abl, which is a tyrosine kinase (this simply means that it is involved in regulating protein activity) and is connected to a form of leukemia, was also active in the brain.  Professor Dawson and his colleagues realized that c-Abl might be "turning off" parkin in the brain and that this was connected to Parkinson's.  If we could block c-Abl from turning off parkin, then maybe we could reverse the build up of protein in cells that we think is important in Parkinson's disease at the cellular level.

Funded through NIH's Udall Centers program, the Dawson Lab started looking at whether c-Abl could be inhibited. Other labs also pursued this target, including animal tests of imatinib and nilotinib, two leukemia drugs -- the latter by a biologist at Georgetown, Charbel Moussa.  The nilotinib results were promising and replicated at another lab.  Moussa found that nilotinib reversed alpha synuclein accumulation in a mouse model of Parkinson's.  The team at Dawson's lab also studied nilotinib, and recommended that a phase I trial be initiated.

Moussa, working with the director of the National Parkinson Foundation Center of Excellence at Georgetown University, a neurologist named Fernando Pagan, launched a clinical trial of nilotinib for Parkinson's.  The results of that trial were presented at the Society for Neuroscience meeting in Chicago this month.  The press focused on the symptomatic benefits, but most scientists will tell you that we can't tell the difference between the the drug effects and placebo effects in a trial like this.  (The story of intravenous glutathione -- positive open label, negative randomized controlled trial -- is an example.)  The best we can say about the phase I trial at Georgetown is that it could have contradicted the very promising animal studies, and it didn't: tests of patients' spinal fluid suggested that the benefit might be real.  [Update: Ted Dawson told the Udall Center Directors meeting that he felt the dose in the Georgetown trial was too low, so it's not clear what we might see beyond placebo benefit. Update 2: Moussa says that the lower dose is effective because we don't need to inhibit c-Abl all the time, just for for a portion of the day, since these cellular processes can occur very quickly. The dose effective in cancer inhibits c-Abl around the clock.]

Further testing is clearly required.  People often say this when they mean, "someone who is widely respected and/or gives out a lot of money has said something and I don't want to contradict them."  In this case, however, I mean what I'm saying: we need more testing.

There is good reason to believe that it is fundamentally possible to slow or stop Parkinson's, and it is possible that if we did that, the brain would recover... somewhat.  The discovery of c-Abl as a target was done through good science, with biology, hypothesis testing and replication and all the good stuff of serious science.  It is possible but certainly not definite that c-Abl inhibition is the path to do this.  However, remember that this is chemotherapy.  Chemotherapy has a bad reputation for side-effects with good reason.  There are other promising studies, too, and we need to trust the scientific process as much as we put our chips on one drug in the pipeline or another.

The Maze of Health Finance

(Originally posted here.)

From the outside, the flow of funds in healthcare appears simple: Society puts money into healthcare and we get out health outcomes and revenue for the healthcare industry.  This simplicity is misleading, however.  It’s easy to think that you’ve figured out how to revolutionize healthcare, based on observing that one simple relationship: we put a huge amount of money into healthcare and get fairly little health out.  In reality, healthcare is a lot more complex.  It is a maze of interlocking financial relationships, contractual obligations, and misaligned incentives.

Let’s imagine a guy named Joe.  Imagine Joe has a dog, Buddy, and Buddy gets sick.  Joe takes Buddy to the vet, let’s call her Michelle. Michelle tells Joe he is in luck. It looks like Buddy has a condition that has been the subject of recent study and a newly developed surgery can help Buddy.  Michelle’s partner, a surgeon, has been trained on the procedure.  Buddy needs a CT scan to figure out whether he needs the surgery.  If the CT scan is positive and Buddy needs the surgery, there’s a 10% chance that the surgery will kill Buddy.  Even if the surgery is successful, in the best case, dogs only live about 18 months after the surgery (that’s about 10 dog-years).  “Wow,” says Joe.  “That sounds expensive.”

“It is,” says the Michelle.  “The CT scan costs $1500.  If necessary, the surgery costs $6,000 and that’s assuming there are no complications.  You could be easily talking $10,000 or more.”

“Gee,” says Joe.  “That’s a lot of money, and I could spend it all and have Buddy die anyway.  Isn’t there a less expensive option?”

“Yes,” says Michelle.  “First off, even if the CT scan is positive, you don’t have to do the surgery.  There’s a chance that Buddy might just have a simple infection, and that’s what the CT scan is intended to rule out.  We could, I guess, skip the CT scan and just give Buddy the antibiotics in the hopes that he just has the infection, but if he doesn’t, he’ll die.”

“Hmmm…” Joe ponders. “That’s more than I saved up all last year.”

---

Now imagine that Joe is your insurance company.  Buddy is you.

It gets more complex.  Maybe Michelle’s veterinary practice has invested in an imaging center.  (The anti-kickback laws don’t apply to veterinarians.)  Michelle’s failure to refer patients for CT scans could affect the imaging center’s ability to make payments on the vendor-financed digital scanner.  Michelle’s partners were planning on the revenue from the imaging center to help pay their now-underwater mortgages.  Daytime use of the CT scanner is reserved for human scans, but insurance companies have negotiated such low reimbursement for scans that the fully-booked daytime use, after expenses, doesn’t cover the payments on the scanner.  The interest rate went up because, thanks to lower reimbursement, the credit rating of the center deteriorated.  The imaging center was relying on nighttime veterinary use in order to achieve positive cash flow.  Should Michelle have hard-sold the scan?  The surgeon in the practice was relying on Michelle’s referrals.  Without the scan, there’s no chance that Joe will even consider surgery.  Michelle, as a partner in the practice, would have gotten a piece of the imaging revenue and a piece of the surgery revenue.  Clearly, Michelle’s and Joe’s interests were not aligned.

Misaligned incentives don’t always result in bad care.  Today I work with a wonderful group of physicians.  Movement disorder neurologists are, in my experience, some of the most patient-focused physicians I’ve ever encountered.  There is a real debate about the value of services that generate tremendous profits for the hospitals that employ many of these doctors, and even some of those physicians who might be under the most pressure to deliver these services seem to be unafraid to express doubt in their value.

Having said this, I also know that there are physicians who do go the other way.  Drug, device, and test companies work hard to develop great products and sell them.  Banks finance capital purchases at hospitals and clinics.  Confirmation bias can be an insidious thing.  If a salesman has extolled the virtues of a drug, scan, or procedure, and, convinced, a physician invests in it, how likely is he or she to tell that patient who might benefit from it to wait and see?  Even more insidious, often the “salesman” is a respected colleague who developed it.  This is the least of the problem, as this scenario assumes an honorable physician: I’ve personally spoken to doctors who unabashedly explain that they make more money from their patients who maintain a moderate level of illness.

As an investment banker, I once got a call from a physician.  He was pitching to me the idea of my helping him raise money for a physician take-over of a failing hospital.  We said, send us the hospital’s financials.  The physician responded, “You don’t need to see the hospital’s financials.  They are terrible.  What you need to do is read Atul Gawande’s New Yorker article on McAllen, Texas.  Physician-owned hospitals make money.  It’s as simple as that.”  We were led to understand that the physicians would want the hospital to be profitable.  Whatever the debt service was going to be, the revenue would be greater.  If, for example, a neurosurgery practice was required for the hospital to get in the black, they’d get one.  Not only that, but they’d make sure it had patients.  I turned away the business; I don’t know if the deal ever got done.  There are rules that limit a physician’s ability to share in revenue from certain sources, but observation suggests that there are ways around this.

For the entrepreneur, these bad apples are actually the easiest to work with, as you can understand their motivations.  It’s the good and well-meaning parts of the system that make reforming medicine so challenging.  When I was a kid, my dentist looked in my mouth, probing my teeth and looking for trouble spots.  It took him 15 minutes.  My daughters’ dentist now has a technician x-ray their mouths. While my dentist used to have a staff of two hygienists, my daughters’ dentist has a staff of six.  My daughters’ dentist spends less than five minutes with her. Is the new way better?  Maybe it is: that’s the problem. I can’t help but noticing that this new way lets my daughters’ dentist charge a whole lot more for a whole lot less time spent per patient.  The sad thing is, between staff costs, negotiated rates and interest payments on capital investment, I wouldn’t be surprised to hear that both dentists, adjusted for inflation, got about the same income.  Yes, there are many new and revolutionary therapies that are changing people’s lives.  However, the major consequence of medicine’s increasing complexity seems to be, in many cases, increased complexity.

Looking for Answers

We all hope some day to be able to stop Parkinson's in its tracks. We want to stop Parkinson's forever, and even reverse the changes in the brain that result in Parkinson's, despite the serious challenges there are in making changes to the wiring of the brain. In my job, I have funded some of the work to make a pill that would stop Parkinson's, including work on the Parkin protein and alpha synuclein.

As I do this work, I am left with a question: what if we already know secrets that will change the course of Parkinson's, or they are right under our noses, and we haven't noticed?  Working with a smart new neuroscience Ph.D., I did some research to identify the impact of exercise on Parkinson's disease.  The results were dramatic.  Regular exercise -- just 2.5 hours a week -- seemed to turn back the clock on Parkinson's by about a year.  We don't have evidence that exercise changes what is going on in neurons in your brain, but we do think that exercise helps the cells in your brain to fight Parkinson's.

That's not it.  In another study, working with the Mayo Clinic's Anhar Hassan, we showed that there are many patients who out-perform the average, living with Parkinson's for 20 years or more.  While some in the PD20 cohort exhibited advanced disease, there did seem to be a group of what we might call "elite controllers" of Parkinson's disease.  These patients have been treated for years by leading experts at top academic medical centers, we think that they really have Parkinson's and are not misdiagnosed.

What if the secret to controlling Parkinson's disease isn't in a test tube in a lab somewhere but is, in fact, floating in the cells of one of these long-term thrivers?  I am hoping to launch a study to determine just this question: are there people whose cells are specially designed to fight Parkinson's, or are their cells deficient in some way that prevents progression?  If we could answer this question, we could then challenge our pharmaceutical company partners to figure out how to deliver this benefit to everyone with Parkinson's.

The first cure for AIDS was discovered in the bone marrow of a man who was immune to HIV.  We can cure "bubble boy disease" with tissue from unaffected people.  Small pox was eradicated using a virus found in nature.  We believe that many of the clues to Parkinson's in humans will be found by studying people with Parkinson's.  Many of the hardest questions for scientists are found to have been solved by nature, if we just knew where to look.

PS: many totally brilliant research findings are coming from biologists and researchers who are looking at molecular, cellular, or animal models of Parkinson's.  However, one of the most exciting findings of the past decade was a result of insight from studying patients who had a particularly bad form of Parkinson's, as I detailed earlier.  Studying people in the clinic and studying drugs in the lab form a virtuous circle.

Linking genes to cell function

In the 1990's, as scientists were conducting the human genome project, there was a belief that knowing the genome would explain all the mysteries of the body.  Once we could decode our genome, we could customize medicine for our unique makeup.

This turned out to be a little optimistic.

Genes contain the codes for proteins, and that's all they do.  Just knowing the code for a protein doesn't tell you much about that protein, though.  Sometimes we are lucky, and we find that a disease is linked to a protein whose function we already knew.  Most of the time it doesn't work like that.

Most of the time, a geneticist will study a group of people who have the same traits and look for common elements in their genes.  The story of alpha synuclein, the protein that many scientists now believe is closely tied to the pathogenesis (i.e., cause) of Parkinson's, offers a nice illustration of how this happens.

As I wrote earlier, alpha synuclein was discovered in 1994.  In 1995, researchers figured out what gene coded for alpha synclein and then, in 1996, a collaboration of NIH researchers with colleagues from the Robert Wood Johnson medical school and Seconda Universita degli Studi di Napoli showed that, in a large Italian family, they could link the family members who developed Parkinson's with a specific genetic location.  Soon after, again under the lead of Mihael Polymerapoulos at NIH, the team showed that this was the gene that coded for alpha synuclein.

Even when it was discovered, Polymerapoulos and his colleagues knew that the mutation they had discovered could not explain very much of the Parkinson's disease that neurologists were treating in their clinics - few people would have that specific mutation.  However, it didn't have to.  Knowing that the gene for alpha synuclein was important meant that it was likely that the protein alpha synuclein was important - but how?  In short order the next breakthrough came from the lab of Cambridge's Michel Goedert and his team: Lewy bodies, known to be present in the brains of people with Parkinson's since 1912, were composed of alpha synuclein.

Since then, further research has shed more light on the puzzle.  A group of leading neurologists figured out that Parkinson's seemed to be transmitted into transplanted cells.  This fueled the development of the prion hypothesis, that Parkinson's disease might be a prion disease.  Northwestern's Dimitri Krainc, when he was at Harvard, tracing the clues from another gene associated with Parkinson's, explained a part of this mechanism.  Others have provided more important clues.  

The importance of alpha synuclein to current research is well documented.  What's important about this story is that the genetic research didn't explain a genetic cause for the 15% of the disease that seems to be hereditary.  Instead, a mystery that started with one Italian family with a rare genetic defect started us on the path to understand all of Parkinson's disease.

The idea that knowing your genes will explain your health hasn't panned out.  Finding a genetic defect that causes Parkinson's isn't important just so that we can make genetic tests.  Understanding genetic defects that are linked to disease can identify mechanisms that are important in those diseases. We originally thought that genetic tests would tell us how to personalize medicine for you.  Instead we are finding that by understanding what genes are linked to aspects of each individuals health, we can identify ways to help everyone.