2013 Medicine Nobel

The 2013 Nobel Prize in Medicine has been awarded to Thomas Südhof, James Rothman and Randy Schekman for their discoveries of how the transport mechanism in cells works.

Cells are the basic units of life. Each of the billions of cells that make up the human body are packed with machinery to help them perform their special roles. Brain cells (neurons), for instance, need to produce and release neurotransmitters to pass important signals to other brain cells. Other key chemicals such as enzymes and hormones also need to be similarly moved.

Before the work of these pioneering scientists, others had discovered that tiny fat globules called vesicles that were involved in the transport system. But little was known about how these vesicles perform their job, delivering key chemicals at the right place and at the right time.

Fascinated by this problem, in the 1970s, Schekman, now at the University of California, Berkeley, worked with yeast cells to figure out the details. He used cells with defective transport machinery to reveal the genes responsible for causing the problems. These genes fell in three classes, each handling a different part of the tightly regulated transport system.

Kathryn Ayscough, a molecular biologist at the University of Sheffield, said, “I still work with yeast cells to understand how cells work. This recognition with a Nobel Prize shows how elegant studies based on simple organisms can reveal intricate details of how all cells work.”

Rothman, now at Yale University, wanted to investigate further. At the time it was believed that the tightly bound space within a cell was somehow responsible in helping each vesicle reach its particular target. But by isolating key proteins that he believed were involved in vesicle transportation, Rothman discovered that the transport system worked perfectly even in a test-tube.

It turned out that the genes identified by Schekman also coded for the proteins Rothman isolated. “Taking different approaches to explain the same phenomenon is often the best way of doing science,” Mike Cousin, a cell biologist at the University of Edinburgh said.

With the cell’s internal machinery somewhat understood, Südhof, now at Stanford University, was interested in finding out how neurotransmitters were released in such a precise manner in neurons. This carefully orchestrated transfer of neurotransmitters is the basis of how our brain functions.

He found that when electrical signals travel along a neuron, they attract calcium ions and enter the cell through temporarily activated channels. These calcium ions activate proteins on the surface of the vesicles, which forces them to fuse with the membrane to off-load their fill of neurotransmitters. Südhof’s work identified the proteins involved in the fusion process.

“Without his work, we would still be looking for the molecules responsible in the fusion process,” Cousin said. Instead, in the years since Südhof’s work was published, researchers have identified that many neurodegenerative diseases, such as Alzheimer’s, are caused by the malfunctioning of fusion proteins.

“The prize-winning work shows it often takes a long time for basic research to be recognised for its impact,” Ayscough said. The researchers set out to understand how a cell works, but their work is now being used to develop medicines for some of the most debilitating diseases.The Conversation

First published on The Conversation.

Image credit: neuroimages

The value of medicine

Drugs

Drug discovery is a long, arduous and expensive process. Is it worth it?

“One minute I was looking at death. The next, I was looking at my whole life in front of me,” said Suzan McNamara, a patient suffering from chronic myeloid leukaemia (CML), a nasty form of blood cancer. She had just heard that she would be receiving doses of imatinib, a drug that had shown remarkable recovery among patients of this cancer. Four decades of research was needed to make this drug, and to enable such a moment for a cancer patient. It is Ms McNamara’s story and that of many others like her that could possibly justify billions of dollars and years of efforts put into discovering drugs.

CML causes unregulated growth of white blood cells leading to pain, debilitating illness, and, before imatinib was discovered, all too often, death. The only options for treatment, before the drug therapy became common, were a bone marrow transplant, which is very risky, or daily infusions of interferon, an artificial way of boosting a patient’s immune system that has severe side-effects.

The process of discovering a drug like imatinib, commercially known as Gleevec, is a long one. First pharmacologists pick apart the workings of the disease and find a pathway that can be targeted. Then chemists design molecules or use readymade libraries of molecules to block (or, occasionally, activate) that pathway. Typically, of the 5000 molecules that showed promise at this first step, on average, only five are deemed safe enough to undergo human trials. Then, after three to six years of clinical testing, only one of those five molecules may become a drug. Finding a drug is literally like looking for a needle in a haystack. All considered, the success rate is 0.02% and it requires more than a decade worth of research at an average cost of $1 billion.

But imatinib was worth it. It was the first drug that could precisely target cancerous molecules. The science that underpins the achievement began with a discovery in 1960. Two researchers at the University of Pennsylvania found that cancerous cells possessed a particularly small chromosome (number 22 out of the 23 chromosomes that make up human DNA), and this was proposed as the cause of unregulated growth. This was the first time that cancer was linked to a genetic abnormality.

How that abnormality led to cancer remained a mystery until new techniques to visualise segments of this chromosome were found in 1973. Then Janet Rowley, of the University of Chicago, showed that the small size of chromosome 22 was due to an exchange of one of its large segments with a small fragment from chromosome 9. The alien material on chromosome 22 now led to the production of a cancer-causing protein. This rogue protein, an enzyme, was involved in the regulation of cell growth. Dr Rowley postulated that blocking this enzyme should stop cancerous cells.

The charge to find the blocking agent was taken up by medicinal chemist Nicholas Lydon, of Novartis, and oncologist Brian Druker, then of the Dana-Faber Cancer Institute in Boston. They needed to find a molecule that will selectively block the rogue enzyme and leave hundreds of useful ones alone. Following the iterations of the drug discovery process, the team took eight years of efforts to find imatinib. In Phase II clinical trials nearly every patient who took the drug felt surprisingly better in a short period of time, which led to a fast-tracked approval for the molecule from the Food and Drug Administration in 2001.

Imatinib was also approved for treatment of gastrointestinal stromal tumours and other forms of leukaemia, too. Earlier this year, Dr Rowley, Dr Lydon and Dr Druker received the prestigious $650,000 Japan Prize given for outstanding achievements that advance the frontiers of knowledge. “Their work shocked the world of clinical medicine”, the prize citation said. Times have changed drastically from early 20th century when patients depended on good fortune, as drugs were often only found serendipitously.

Ms McNamara was diagnosed with CML in 1998. By the time she received imatinib through a clinical trial in January 2000, her condition had become quite severe. “I was basically on my last limb,” she recalls. Before imatinib was discovered, only three out of five CML patients survived for more than five years after diagnosis. But a 2011 study showed that even eight years after diagnosis, only 1% of CML-related deaths occur among patients using the wonder drug.

With her health restored to normal, Ms McNamara went on to get a PhD in leukaemia research. Quite early in her studies she realised she may not be the one to cure leukaemia herself, but she said, “I might publish one paper that has one key for the next person to go a step further. That’s important”.

Drug discovery is a long, arduous, and expensive endeavour, but it is a process that is being continuously refined to produce results faster and more cheaply. Researchers consider themselves fortunate if they witness the successful launch of a drug in their lifetime, but extraordinary stories of patients motivate them to keep improving this process and searching for that elusive molecule.

Free image from here.

Self-medication: When waiting is not an option

It takes eight years on average for a drug to receive approval from America’s Food and Drug Administration (FDA) after clinical trials have been successfully completed. Some patients of amyotrophic lateral sclerosis (ALS), with a life expectancy of two to five years after diagnosis, do not want to wait that long. Since September 2011 some of those diagnosed with the fatal disease have taken to injecting themselves with a substance whose chemical identity they deduced from published literature, and which they claim is currently being clinically tested.

Also known as Lou Gehrig’s disease, ALS, for which May has been the awareness month in the United States since 1992, causes rapid nerve-cell damage in the brain and spinal cord leading to a loss of muscle control. Breathing and swallowing are usually among the first to be affected, significantly reducing the quality of life. Although using substances which have not been approved by regulators like the FDA can be dangerous, easy availability of scientific literature and online support groups to swap usage information, more people with rapidly-progressing, fatal diseases like ALS are second-guessing drug makers.

In November 2010 Neuraltus Pharmaceuticals, an American firm developing ALS treatments, reported positive “phase I” trials for the drug codenamed NP001. (Phase I is the first of three stages of human clinical tests in which the drugs are primarily screened for safety.) Based on published papers and patents, Eric Valor, an ALS patient who did not participate in the trial, concluded that NP001’s active ingredient is sodium chlorite, a chemical used mainly in bleaching paper pulp or to disinfect water.

Although Neuraltus is still keeping the true identity of NP001 under wraps, Mr Valor’s conjecture prompted a number of patients, including some who had participated in the NP001 trials, to start taking sodium chlorite last September. They also began sharing data on dosage, therapeutic effect and side-effects on sites like PatientsLikeMe. In effect, they conducted a crowd-sourced clinical trial.

When pharmaceutical companies test a drug’s efficacy they tend to plump for randomised, double-blind trials. They are randomised because patients who get the medication and those who receive a placebo are drawn at random, eliminating selection bias, and double-blind because neither the patient nor the doctor knows whether the substance administered is the real thing or a sugar pill.

Self-medicating groups like those on PatientsLikeMe clearly lack such controls. However, in a paper published last year in a respectable journal, Nature Biotechnology, the founder of PatientsLikeMe, James Heywood, and his colleagues showed that randomisation can be mimicked by feeding results from patient networks into clever algorithms; though such pseudo-randomised trials still lack blinding and are therefore no substitute for fully fledged clinical research like that being undertaken by Neuraltus for NP001, whatever its actual composition.

Mr Heywood’s piece of citizen science showed that another substance, lithium carbonate, was ineffective in treating ALS, a result confirmed by traditional trials. Sodium chlorite may yet suffer the same fate. That is a risk some ALS patients are willing to take.

Also published on economist.com.

References:

  1. Neuraltus Pharmaceuticals press release
  2. James Heywood et al. Nature Biotechnology, 2011
  3. Eric Valor’s conjecture
  4. ALS Study Shows Social Media’s Value as Research Tool – The Wall Street Journal
  5. Frustrated ALS Patients Concoct Their Own Drug –  The Wall Street Journal
  6. PatientsLikeMe – Lithium and ALSsodium chloriteNP001
  7. ALS Chlorite

 Image credit: The Economist