From
The Observer in the UK. In the picture, Dr Bill Gahl, left, talks to Chris and Kelly Klodzinski about Kelly's symptoms at the NIH in Bethesda.
The US National Institutes of Health are using pioneering genetic techniques to diagnose mystery illnesses that afflict the lives of untold thousands.
DeGalynn Wade graduated as a lawyer in 1998 and began work as a prosecuting attorney in Minneapolis. "Life was perfect," she recalls. "I had a cute car, a cute condo – a cute life. I was a lawyer. I made headlines." She started to experience occasional blurring of her vision in her right eye. Doctors thought she could have multiple sclerosis and gave her drugs to treat the condition. They had no effect, though the young lawyer was able to continue to work. "My left eye was compensating for the loss of vision in the right," she says.
In 2002, Wade married a fellow lawyer, Lance Sanders. "It was a fabulous wedding but by then my vision was deteriorating seriously and very soon I found I couldn't drive. I had to give up my car and start taking the bus. One day, someone I had prosecuted came up to me and started pointing and cursing at me, but I couldn't even see her. I couldn't see my clients. In the end, I had to leave prosecution law."
Today, Wade – an elegant and resolutely cheery 38-year-old – is registered as legally blind and her once perfect life has been altered in a grim manner. She is blind but doctors do not understand why. The neurological changes that are responsible for her condition remain a mystery.
"Her loss of vision is her only symptom," says neurologist Dr Camilo Toro, of the National Institutes of Health (NIH), in Bethesda, Maryland. "That is strange. In multiple sclerosis, for example, many other symptoms are displayed: problems of gait, balance and changes to other sensory organs. She has none of those. Ten years ago, her diagnosis of multiple sclerosis was a reasonable one. But that is no longer tenable." Magnetic resonance images of her brain are also very unusual, adds Toro. "There are alterations in her occipital region and nowhere else. Many other diseases produce blindness but none of them does so without producing other symptoms. DeGalynn has no other symptoms."
In short, DeGalynn Wade has lost her sight for no discernible reason. She is a victim of an illness that appears to be completely new to science. Hence her involvement with a remarkable new scientific project, the NIH's undiagnosed diseases programme headed by geneticist Bill Gahl. Based at the institutes' giant complex of research buildings and hospitals in Bethesda, outside Washington, some of America's top medical experts, including Camilo Toro, have joined forces, under Gahl's leadership, to exploit the formidable techniques of modern genetics and medical scanning to pinpoint conditions whose causes continue to mystify doctors. Some of the most baffling medical problems on the planet are sent here for solution.
It is a bit like House, the TV series in which the curmudgeonly diagnostics expert played by Hugh Laurie is sent patients with perplexing conditions – but only a little bit, says Gahl. Laurie's character is an arrogant egomaniac who solves every case as if by magic, he says. By contrast, work at the programme is a highly disciplined team effort which produces a breakthrough in only a small fraction of the complex cases they investigate. Nevertheless, each success represents a significant advance for modern medicine.
"We opened a couple of years ago and now have the medical records of 1,300 individuals," says Gahl. "In some cases, it becomes fairly clear that something has been overlooked and we are dealing with a known disease. We send those cases back. In others, we have found that we are dealing with an unusual and medically interesting variant of a relatively rare but already known condition. And then there is that one case in 50 that represents a completely new illness."
In other words, out of the 1,300 cases now being studied on the programme, several dozen new diseases should soon be identified and their exact aetiology unravelled. How long it will then take to develop new drugs for treating these conditions is not so clear. Gahl remains hopeful, nevertheless.
Bill Gahl is a slightly built figure with thinning grey hair and frameless glasses. He is smartly dressed and assured, though his speech on the day of our meeting was strained and his words half-swallowed, the result, it transpired, of Gahl having had his jaw wired together a few days earlier following a softball match in which it had been broken. "I play a hard game of softball," he explains.
He was asked to set up the undiagnosed diseases programme in 2008, in addition to his other job as a clinical director at the NIH, and was given a staff of three to run it. The aim was simple: to use the expertise of the doctors of the NIH, one of the world's leading medical institutions, to unravel the causes of conditions that were continuing to baffle science. Patients would be brought in for a week of intense tests and the results analysed using the NIH's geneticists, cardiologists and other experts.
Work began in May and within a couple of months, the programme's office was overwhelmed with cases. "I went to the head of the institutes and asked him to suspend the programme because we just couldn't handle the caseload," says Gahl. "He responded by giving us more money. It would have been too embarrassing to shut down so soon after our launch."
In fact, the programme fills an unmet need, Gahl admits – "at least in this country and, quite frankly, in the entire world". As he adds: "Our aim is to help patients with undiagnosed diseases because they have, effectively, been abandoned by the medical profession. In addition, the insights that we get from these cases are sometimes pretty phenomenal."
The trick is to select those who have an affliction that is genuinely new – for many who contact the programme are only one step away from hypochondria and include dozens of cases of chronic daily headache and of Morgellons syndrome, a delusional parasitosis whose sufferers believe they have insects crawling over their skin. "Anyone can apply to this programme, as long as they get a doctor's letter," says Gahl. "So we get a lot of crap though the doctors usually send a cover letter that begins with the line saying, 'Mr Smith has asked me to write this letter' or, later on, 'Mrs so-and-so thinks she has an undiagnosed disease'. That's very helpful."
Once a case is accepted, notes are called in and medical histories and CDs of scans are studied before the patient is asked to come to the NIH, where he or she will be subjected to a barrage of MRI scans, genome analysis and other tests. Detailed examination of these may reveal the feature or symptom that will crack the case.
It's a lengthy business and the programme's output of papers has – until recently – remained low and relatively modest. The NIH scientists discovered the first American case of a condition known as CHST-14 deficiency whose patients suffer malformations of the thumb and foot and are afflicted by haematomas – pockets of blood that build up under the skin. In addition, their scientists found the second and third cases in the world of a condition known as congenital disorder of glycosylation type 2B, which causes a range of severe malformations and cognitive problems.
This year, however, the real detective work has begun to show results. "We were contacted by a patient from Kentucky," says Gahl. "She had a very strange set of symptoms: the calcification of large blood vessels and joints in her hands and feet. I looked at her x-rays and it wasn't hard to decide to bring her in. No one had seen anything like that before. Then we found out a sister was affected and later on a further three siblings."
Gahl mentioned the case to a colleague in London who said he knew of similar cases in Italy in which patients were suffering from unusual deposits of calcium in their veins and arteries. This work was presented at the American Society of Human Genetics last October, where another doctor recognised the symptoms, this time from a woman living in San Francisco. "So we had this strange calcification of blood vessels and joints in five individuals in a Kentucky family – all adults in their 40s and 50s and products of a third cousin marriage – plus an Italian family plus a San Francisco woman," says Gahl.
The question was: could the scientists pinpoint the common cause of the condition affecting all these individuals? They took tissue samples and, using a gene analysis technique known as a million snp array analysis that has been pioneered in the wake of the Human Genome Project, they subjected the patients' DNA to detailed study to identify any unusual features. They did: on chromosome 6, one of the packets of genetic material that directs the growth and organisation of the cells of our bodies. The team spotted a section containing 92 genes that seemed to be linked to the condition. One of these 92 genes appeared to be the culprit. The team's cardiology researcher Manfred Boehm then picked three of these genes as the most promising candidates as causes of the condition. Within days, one of them found to be responsible.
Those affected by the calcification disease possess a pair of chromosomes 6 – chromosomes come in pairs inside our cells – that contain the aberrant gene that had been pinpointed by Boehm. Such a disease is said to be recessive.
It was a striking breakthrough. Not only had the team discovered a completely new disease, but they had identified a previously unknown chemical pathway that can lead to calcification of the body's organs. The exact details of this pathway will be revealed shortly in a paper which Gahl and his team have written for the New England Journal of Medicine. However, the work is already causing excitement among doctors.
"We think this new condition is important for two reasons," says Gahl. "There are cases where patients suffer calcification of kidneys or spleen or other organs and doctors simply do not know why this has occurred. Our work suggests a possible cause. Second, some people do not have proper calcification of their bones and again doctors do not always know why that is. So, it could be that the pathway we have discovered is playing a role. The crucial point is that none of this work could have been done without the techniques of gene array analysis. They have transformed our ability to pinpoint medically important pieces of DNA. What once took months or years now takes days, if not hours."
These ideas are intriguing, although they do not suggest that treatments for these conditions are going to be available overnight. A great deal of work lies ahead, a point that is not lost on other patients who attend the NIH in search for knowledge about their conditions. This is a completely new approach to tackling disease with an unproven track record, a point accepted by DeGalynn Wade.
During her week's stay at the NIH, she was subjected to a catalogue of medical experiments: lumbar punctures, magnetic resonance scans, blood samples, brain wave measurements, among other procedures. In addition, her genome was analysed in detail. The results of these probes are being studied by experts at the NIH to try to determine why she has gone blind in such a mysterious manner. No one expects the task to be easy. Nevertheless, with a few recent successes under their belts, the team are confident of future successes.
"I am just hoping for some clarity," Wade says. "The idea that I will go home and take a blue pill so that everything is going to be OK is a dream. I know that. I am just happy to be here though it would be wonderful if I could get some answers to my problem."
Such a reaction is not typical among their patients, says Gahl. "It is not actually such a good thing to be here. It means you have something that people cannot figure out. That is the sobering part of this."
But Wade insists she is lucky to be involved with the programme. "I know a lot of people would love to come to NIH to receive any kind of potential treatment or get answers to their medical problems. So I am grateful. In the end, I just want the world to know about anything that can be learned from me."
The key technology employed at the undiagnosed diseases programme is known as a one million SNP microarray. Using the technique, which is only a few years old, it is possible to determine key differences between two people's DNA in a very short time and so determine why one individual is suffering from an inherited condition while another person is not.
SNP stands for single nucleotide polymorphism and refers to a single point on a particular stretch of DNA that can differ between people. Microarrays enable researchers to capture over a million different SNPs in a single individual. The genetic basis for a particular disease can be revealed if the DNA from a large number of individuals with and without that disease is compared across many SNPs using microarrays.
To use the technique, a patient gives a sample of blood. His or her DNA is then extracted from the white blood cells in that sample. Then the DNA is copied millions of times using a technique called polymerase chain reaction (PCR). Then that DNA is added to a chip containing specific genetic probes that bind to a specific SNP. Fluorescent tags then reveal which version of a particular SNP an individual is carrying.
"The key point is that we can do this sort of analysis very quickly and relatively cheaply," says geneticist Carl Anderson of the Sanger Institute in Cambridge, where scientists funded by the Wellcome Trust are working on a range of new investigations of human disease. "This technology has revolutionised human genetics in the last few years," he adds.
