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Why Rare Diseases Will Help Us Solve Common Diseases

January 9, 2009 by  
Filed under Health Care Policy

Francis Collins

The Key To The Closet Is The Key to the Kingdom: A Common Lesson of Rare Diseases

How can understand more about the most common diseases that affect mankind.  By looking at the rarest diseases. This story takes us back……

Nearly twenty centuries ago, the Roman poet Juvenal wrote in The Satires about “a rare bird comparable to a black swan.” The notion of rarity enticed the mind in antiquity, and continues to do so in modernity – in medicine and in our daily lives. What are the lessons of rarity and specifically of rare diseases? Let us look closer and observe.

The place was London. The date – April 24, 1657. A letter arrived at the home of Dr. William Harvey, a man whose life was distinguished by one of the greatest discoveries in the history of medicine, the discovery of the circulatory system. But, the letter to Dr. Harvey from a Dutch physician, John Vlackveld of Harlem, had nothing to do with common problems of the heart or blood or circulation. The letter invited Dr. Harvey’s attention to the case of a gentleman with an extremely rare affliction of the urinary bladder. Dr. Harvey was old and in failing health, and could not assume the challenge, but he clearly recognized the value of such a noble pursuit. He reached for a piece of parchment, dipped his pen in the inkwell, and wrote these words: “Learned Sir, your much esteemed letter reached me safely in which you not only exhibit your kind consideration of me, but display a singular zeal in the cultivation of our art. The case of the plasterer to which you refer is indeed a curious one, and might supply a text for a lengthened commentary. But, it is in vain that you apply the spur to urge me at my present age to gird myself for any new investigation.”

While unavailable, Dr. Harvey, however, was not disinterested. He continued the letter in what might arguably be one of the most prophetic passages ever written in the history of medicine:

“It is even so,” he wrote, “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature by the careful investigation of cases of rarer forms of disease. For it has been found in almost all things, that what they contain of useful or of applicable nature, is hardly perceived unless we are deprived of them, or they become deranged in some way.”

Centuries later, in an address delivered to The Medical Society of London on May 21, 1928, Sir Archibald Garrod, the father of metabolic disease, cited that monumental letter from William Harvey. In an engaging essay entitled, “The Lessons of Rare Maladies,” published in The Lancet the following week, Dr. Garrod paraphrased, “The study of nature’s experiments is of special value; and many lessons which rare maladies can teach could hardly be learned in other ways.”

Francis S. Collins, M.D., Ph.D., (Former) Director of The National Human Genome Research Institute said more recently, “While many of the genes we will initially be pursuing are responsible for rare disorders, what we learn from rare disorders often has profound consequences for our understanding of more common conditions.” But, why is that so? Why are rare conditions so instructive of more common ones?

To begin, rare diseases provide robust insight into complexity in biological systems. The specificity of the rare disease often permits a causative genetic factor to be isolated in a complex regulatory network, thus identifying and defining the network itself. Such insight is often the catalyst for dissecting the structural organization and/or inter-dependent signaling networks that are influenced by common genetic variations and that lead to some of the most common diseases of mankind. Nature does not use different genes, molecules, and pathways for common conditions than it does for rare ones. Rather, it is often the rare disease that actually reveals which gene, molecule or pathways nature hijacks in its common infirmities. The key to the rare disease is often the key to the common one. The key to the closet is often the key to the kingdom.

As examples, studies of familial hypercholesterolemia, Lesch-Nyhan disease, fibrodysplasia ossificans progressiva, congenital malignant osteopetrosis, and Hutchinson-Gilford progeria, all exceedingly rare conditions, have revealed the causative genes not only for each of these rare disorders, but have also illuminated the molecular pathways for common disorders of cholesterol metabolism, uric acid metabolism, heterotopic ossification, osteoporosis, and aging respectively – diseases that in some cases affect tens of thousands of people worldwide, and in other cases, millions.

The examples, iterations and lessons of rare maladies are profound and endless. In a dazzling article on “a new grammar for drug discovery,” (Nature 437: 491-493, 2005), Mark Fishman and Jeffrey Porter discuss the value of rare diseases not only for illuminating common conditions, but also for drug discovery. “Historically pharmaceutical companies have not focused on these diseases, in some cases because the affected protein is not tractable to pharmaceutical approaches, and in others, perhaps, because the number of people affected is small. But, the powerful role of a single gene in Mendelian disease can provide insight into complex diseases where the same gene accounts for part of the phenotype. Statin therapy, for example, was initially directed to patients with a genetic predisposition to excessive levels of blood cholesterol. But after the drugs efficacy and safety had been tested, the treatment was extended to a wider population of patients who had the same condition but due to many causes.” Once again, the key to the closet is the key to the kingdom.

In the last paragraph of his essay (The Lancet; May 26, 1928), Sir Archibald Garrod states, “We may feel sure that, in the future as in the past, there will be many who will try to solve the problems of the commoner diseases, the control of which is of vital interest to the community at large. Let us hope there will always be some who will seek to guess the riddles and to learn the lessons of rare maladies.” The implication, of course, is that in doing so, one may provide the clues to solve the more common conditions as well. How ironic and fortuitous that nature would construct such a universal key and place it not in the hands of the king, but in the hands of the custodian. The key to the closet is the key to the kingdom.

And, so we will end where we began with the letter from Dr. Harvey to Dr. Vlackveld, long before the era of gene identification or molecular discovery or recombinant technology. It was almost 350 years ago in London, when Dr. Harvey wrote those words that have not been improved upon since. “It is even so. Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature by the careful investigation of cases of rarer forms of disease.” The key to the closet is the key to the kingdom. It is even so.

Written by Frederick S. Kaplan, M.D.

Re-Thinking Drug Development Roadmap In United States

March 21, 2008 by  
Filed under Health Care Policy, Virtual BioTechs


No Insurance. No Money. No Drugs. No Hope.

We Need A New RoadMap For The Future

Of 7,000+ diseases that affect humankind, treatments for only 200 of these diseases are being actively pursued by pharmaceutical and biotechnology companies. With the cost of bringing a new drug to market now exceeding $1 billion dollars and taking up to 10+ years to test and develop, global pharmaceutical companies are focused on return on investment.

Meanwhile, millions of people suffering from all types of diseases will never see new drugs reach them or their loved ones in their lifetime. As a nation, we must unite to think about the drug development process in a different way and push for change.

Today, one family is faced with paying $180,000 a year for a highly experimental drug treatment for their two children afflicted with Niemann Pick Type C. Who can afford a single experimental drug at this price?  Like millions of others, many Niemann Pick Type C children have no health insurance.  No insurance. No money.  No drugs.  No hope.

The dire situation we are faced with our drug development process is happening across disease states — this is not a unique problem to Niemann Pick Type C. The FDA is in a major crisis and we can no longer continue on this path when millions of lives are at stake. The Addi and Cassi Fund, named in honor of our five year old identical twin girls, plans to bring attention to the drug development crisis and to push for change.

We are building one of the first “Virtual Pharmaceutical” models in the United States with the help of Silicon Valley heathcare company CollabRx. Our Virtual Pharmaceutical is named "SOAR-NPC" (Support Of Accelerated Reserach for Niemann Pick Type C) and we are focused on creating a drug therapy pipeline for NPC afflicted children around the world. If global pharmaceutical companies and the FDA won’t help us save our children by rapidly bringing new drugs to market, we must find solutions ourselves in order to attack and treat a rare and fatal disease like NPC.

One of the greatest resources we have as a nation is our National Chemical Genomics Center. The robotic technology at the NCGC which is pictured above should continue to be invested in by our government — NCGCs technology can find existing drugs sitting on shelves that can be repurposed and used to treat diseases they were not originally intended for. Currently, we are funding the NGCG to test thousands of approved drugs as well as natural supplements against multiple Niemann Pick Type C cell lines in the hopes of finding immediate targets to treat afflicted children.

Every dollar donated to The Addi and Cassi Fund goes directly to cutting edge research projects to rapidly accelerating finding immediate treatments for brain diseases. Translational research – studies that bridge the gap between the discoveries in the laboratory with the need to find ways to intervene in the disease process and treat patients who are living with illnesses – is the roadmap for the future. With your help, we can build this roadmap and prove there are alternative approaches to the current drug development process.

We must seek treatments today and cures tomorrow!

The “Lucky 200” Health Care and Drug Club

January 27, 2008 by  
Filed under Health Care Policy


Are you lucky? Did you know that of the 7,000+ diseases that affect humankind, treatments for only about 200 are being actively sought by pharmaceutical and biotechnology companies?  Crazy, isn’t it?  As it turns out, it costs about $1 billion for a pharmaceutical company to bring a new drug to market so they are entirely focused on return on investment. It also can take from 10+ years to get them to market.

This is why we see drugs like Viagra coming on the market and not medicine that can actually cure people who are sick. Which bucket do you think you might end up in someday?  The 200 Club or 7,000 Club?   Why are the political candidates not talking about this topic? You can have all the healthcare insurance you want, but if there is not a drug for you when you become sick, what will you do?

Nearly 47 million Americans, or 16 percent of the population, are currently without health insurance according to the National Coalition on Health Care.   Even if we were able to provide all these uninsured people with health care, the concept of universal health care will never work in a broken system that is full of insane regulations and bloat.

If politicians like Barack Obama or Hillary Clinton want to know what is wrong in the medical system, they should ask people like us who are in the midst of a medical battlefield and trying to win a war.  You can’t understand what is going on until you are fully immersed in this nightmare like we are.  The first thing I would tell them is that $160,000 dollars per year for an experimental drug for two children is a little excessive, don’t you think?

We have only been navigating the medical system for three months — here are some other major problems.

  • Lawyers: everyone in the medical system is afraid of lawyers and paralyzed as a result. The system can’t move and doctors won’t take risks because lawsuits is all they can see.  They are afraid to dispense an aspirin to kids who are dying.  Seriously.
  • Insane Federal Regulations put the fear into Institutional Review Boards (IRBs): we need tort reform on a national level. I had someone smart tell me that what is happening in our system is “criminal.” Doctors and scientists are sick of IRBs and goverment regulations because they can’t get anything done
  • The IRBs Themselves – They are insane: The red tape and paperwork are standing in the way of getting to cures and treatments.  Everyone in the system is complaining about the IRBs – they were designed to help people and protect people and now they are killing people. By the time researchers get IRB approval, their grants have run out. I have been in an IRB nightmare for 3 months with the NIH and our local hospital to get simple samples of urine and blood from healthy kids to compare to Addi and Cassi.  There are plenty of other insane examples that I will post in future blogs.
  • Wrong Incentives – Publish or Perish: Research labs are competitive — all they can think about is their next grant and putting food on the table. Many are running the same experiments and do not talk or collaborate well. There is tons of waste in the system because of lack of data sharing.  Scientists are afraid to put ideas out for fear of ridicule by others scientists and before numerous tests are done 50 times to confirm they are not crazy. Getting information out to the medical community and public is a major bottleneck – the incentives for science needs to change! Future Nobel Prizes should not be given out to scientists or researchers who are not collaborators
  • Technology – many of the people in medicine are still folks who “dictate” and don’t know what a Blog is. Old timers are resistant to change but have the most experience, new scientists are technology savvy but need exceptional tools to make their lives easier. The right kinds of technology need to exist to make it easy for the medical industry to do their jobs
  • Collaboration:  it’s practically nonexistent across the entire medical field
  • Cross Sharing Among Disease States: It’s not simply collaboration between scientists in a particular disease state, it’s creating collaboration between scientists working in different disease states that have connection points
  • Therapies Now: how do you translate what is in petri dishes and mice into potential therapies for people with diseases?  How do you take existing drugs and test them against disease to see if they work or could be used “off label.” Studies in labs with mice do not translate well for people who are dying
  • Case Manager: I am working full time to move the needle for Addi and Cassi. What happens if you have cancer and don’t have an advocate to help organize all of this or can’t get out of bed? There could be a whole business spun out of this idea and people would pay for Case Managers
  • Money: If you want to live, start saving now. You better be prepared to shell out as much money as you can in a broken system.  Not only do you need insurance, you need your own money ….. and lots of luck!

A Law Against Lawyers!

December 30, 2007 by  
Filed under Legal

I am posting this message to the entire world to let everyone know that Hugh and I will not sue any doctor, scientist, researcher, hospital or non-profit if anything happens to Addi and Cassi as we embark on trying experimental treatments to save them from Niemann Pick Type C disease.  No matter what happens during this journey, we assure you we will not take legal action against you and we are putting this is writing for the world to see.  We are also willing to sign any release form necessary.  Of course, this release form would need to be drawn up by lawyers!

Oh, the lawyers!  There really needs to be a law against lawyers. The entire medical system is paralyzed because everyone in the ecosystem is living in fear of litigation.  I can tell you that the medical system as it is working today is keeping children like ours from getting the types of treatments they desperately need.  It has come to the point where doctors can’t even dispense an aspirin or an antibiotic out of fear of malpractice.  There are too many bureaucrats who in turn are afraid of the lawyers and who literally want to stand in our way of getting productive treatments accomplished.  I have come to understand that there are people in the medical and research system who do not want to help us, they simply want to keep their jobs and not get sued or are interested in publishing their next scientific paper.

Then there is someone like Mike Alonso at Jones Vargas, a lawyer who has been particularly helpful in making connections for us during this most difficult time.  Talk about world-class.

And of course there is Dr. Marc Patterson, Addi and Cassi’s pediatric neurologist from the Mayo Clinic.  Every single doctor in America should take a lesson from Marc Patterson on how to care for patients and what it means to be a doctor.  Someone who you would expect would have a huge ego since he is one of the brightest people on the planet does not have one.   I have not met one person who has not said, “Marc Patterson and wonderful” in the same sentence.

Dr. Steve Walkley at Einstein University and Dr. Dan Ory at Washington University who are true collaborative research scientists, who believe in openness, data accessibility and science for the people.  These are a few of the people who keep me hopeful that even despite the lawyers and the bureaucrats and the sickness that exists throughout our medical system, there can be a new paradigm for how rare diseases like Niemann Pick Type C are treated and cured in the future.

“I” for Insane, “R” for Ridiculous, “B” for Broken – America’s Institutional Review Boards

December 19, 2007 by  
Filed under HealthCare


Regulations, Regulations, and more Regulations!

Some people have asked me why I am not blogging about different topics every day. I really wish I could be blogging more but besides having 1000 things on my to do list, I am actually scared to death to actually talk about some things that are happening to us right now out of fear we might not get the help and cooperation we need to try and save Addi and Cassi’s lives. There are many doctors, researchers and scientists who are being highly cooperative and it has been a truly remarkable experience. Thank you!

On the other hand, there are others who are not as cooperative. I have found that there are a lot of major egos in the medical and science community. A lot of science is about publishing papers about experiments in mice and petri dishes, not about finding near term treatments and therapies that can save the lives is kids like Addi and Cassi. The system is certainly not designed around sharing and collaboration – it’s really a collection of silos all competing against each other for funding or who will get the next Nobel Prize. Someday I will have the opportunity to explain more.

What I can and will talk about is IRBs – in my mind the term stands for "Insane, Ridiculous and Broken" ethics oversight committees. I had never even heard of the term “IRB” until a few months ago when a doctor said we have to, “get this idea through the IRB and this is going to take lots of time.”  An institutional review board (IRB), also known as an independent ethics committee (IEC) or ethical review board (ERB) is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the research subjects if they are involved in research studies.

One of the biggest problems we are facing at the moment with Addi and Cassi centers around the IRBs. These IRBs now standing in the way of Addi and Cassi getting critical tests done which will ultimately lead us to therapies more quickly. The bottom line is that IRBs are severely impeding progress of medical research in the United States today and something needs to be done about it at a national level.  I know my rights and I want testing done.

Let me give you an example of just how ineffective an IRB can be when you are facing a rare and fatal disease like NPC and you’re in a sprint, not a marathon, to save your kids lives. The National Institutes of Health (NIH) needs spinal, blood and urine samples from healthy children to compare against NPC children who they are currently studying. Both Addi and Cassi are in the study. If the NIH can compare normal kids samples directly against NPC kids samples, they might actually find something called a biomarker (a sign of illness in the bodies of NPC kids). Piece of cake to get samples, right? Wrong. The problem is it can take MONTHS to put together a “protocol” and get it approved through an IRB. Once you get a “protocol” designed, you need to get group of committed physicians (most likely ER doctors) who will be at the front lines to get consent from families to obtain these specimens.

I have been working with the NIH and my local hospital, Renown Regional Medical Center, to try and make this happen.They both have been very cooperative and are trying to move as quickly as possible under the rules but I’m now seven weeks into this process between getting the protocol, the consent form, and begging our local doctors to participate. I still have to get approval from the local IRB so cross your fingers. Why am I even having to do this? If I don’t do this, it will take months, if not years, to get these samples because there are not enough resources in the NPC community to accelerate the process more quickly.

I told this story to a friend who offered to send her child down to get the blood and urine sample done so we could send them to the NIH immediately. Problem is, you can’t do this, it’s against the "rules."  So while millions of samples are being flushed down the toilet or disposed of on a daily basis at hospitals around the country, kids are dying. These samples literally could provide clues into Niemann Pick Type C that could lead to treatments more quickly. 

This is an absolute nightmare of all nightmares. No parent should be faced with getting a diagonosis of Niemann Pick Type C and then enter into a totally dysfunctional medical and drug development system on top of it. While I realize that IRBs do serve a purpose, the regulations have simply gone too far and therefore are becoming ineffective. It seems like IRBs are far more worried about litigation when they should be focused on saving lives.

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