Author: Akshat Rathi

Akshat Rathi is a senior reporter for Bloomberg News. He has previously worked at Quartz, The Economist and The Conversation. His writing has appeared in Nature, The Guardian and The Hindu. He has a PhD in chemistry from Oxford University and a BTech in chemical engineering from the Institute of Chemical Technology, Mumbai.

The value of medicine

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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.

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Grim and bear it

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The subjective study of suffering

 

Controversy about pain relief is usually between those who worry about addiction, black markets and over-prescription, and those who just want patients with long-running or fatal diseases to get the best pills. But a lesser-known issue is gaining attention, too: the treatment of acute pain.

 

Despite big advances in medical care in most other respects, pain relief after surgery has not improved in the past 60 years. A study in 2003 found that 80% of adults reported moderate to severe pain after surgery, just as many did in 1950. Pain does not just cause anguish: the stress-hormone cortisol it releases can damage the body. The end result may be heart attacks or internal blood clots.

 

The dispute is not about the drugs themselves, but concerns their type, quantity and timing. Medical opinion is surprisingly divided on this, chiefly because it is so hard to measure pain accurately. Attempts to determine a global pain scale have failed, because pain tolerance varies from country to country. In nations with stiff upper lips, a dose may be too high. In those with trembling lower ones, the same amount may be too little. Stereotypes are misleading: on average Germans, for instance, rate pain for similar conditions worse than Spaniards or Italians do.

 

Such comparisons are rare, but a global study called Pain Out is trying to make them more systematic. It records data across 16 rich and poor countries. Patients fill in forms after operations and doctors make notes of given treatments. The data are fed into a central server and can be accessed freely by researchers. In Berlin this month Ruth Zaslansky, of the Jena Medical Centre in Germany, will present the results of the study and actions taken.

 

One finding is that Rwandan women undergoing Caesarean sections get worse therapy than those in any other rich or poor country. As a result, says Antoine Bahati Kabeza, an anaesthetist at Kigali University Hospital, the medical staff are changing its pain-relief policies, and the university is changing the way it teaches pain management.

 

Medical care inevitably varies between rich and poor countries. But pain relief, administered correctly, costs relatively little given the good it does. The psychology of national character does not feature in pharmacological thinking. Perhaps it should.

First published in The Economist. Also available in audio here.

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Gene therapy

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A technique intended to eliminate mitochondrial diseases would result in people with three genetic parents

Is it possible for a child to have three parents? That is the question raised by a paper just published in Nature by Shoukhrat Mitalipov and his colleagues at Oregon Health and Science University. And the answer seems to be “yes”, for this study paves the way for the birth of children who, genetically, have one father, but two mothers.

The reason this is possible is that a mother’s genetic contribution to her offspring comes in two separable pieces. By far the largest is packed into the 23 chromosomes in the nucleus of an unfertilised egg. In that, she is just like the child’s father, who provides another 23 through his sperm. But the mother also contributes what is known as mitochondrial DNA.

Mitochondria are a cell’s power-packs. They convert the energy in sugar into a form usable by the cell’s molecular machinery. And because mitochondria descend from a bacterium that, about 2 billion years ago, became symbiotic with the cell from which animals and plants are descended, they have their own, small chromosomes. In people, these chromosomes carry only 37 genes, compared with the 20,000 or so of the nucleus. But all of the mitochondria in a human body are descended from those in the egg from which it grew. The sperm contributes none. And it is that fact which has allowed doctors to conceive of the idea of people with two mothers: one providing the nuclear DNA and one the mitochondrial sort.

The reason for doing this is that mutations in mitochondrial DNA, like those in the nuclear genes, can cause disease. These diseases especially affect organs such as the brain and the muscles, which have high energy requirements. Each particular mitochondrial disease is rare. But there are lots of them. All told, there is about one chance in 5,000 that a child will develop such an inherited disease. That rate is similar, for example, to the rate of fragile-X syndrome, which is the second-most-common type of congenital learning difficulty after Down’s syndrome. Mitochondrial disease is thus not a huge problem, but it is not negligible, either.

New batteries, please

To find out whether mitochondrial transplantation could work in people (it has already been demonstrated in other species of mammal) Dr Mitalipov collected eggs from the ovaries of women with mutated mitochondria and others from donors with healthy mitochondria. He then removed the nuclei of both. Those from the healthy cells, he discarded. Those from the diseased cells, he transplanted into the healthy cells. He then fertilised the result with sperm and allowed the fertilised eggs to start dividing and thus begin taking the first steps on the journey that might ultimately lead to them becoming full-fledged human beings.

Nearly all of the experimental eggs survived the replacement of their nuclei, and three-quarters were successfully fertilised. However, just over half of the resulting zygotes—as the balls of cells that form from a fertilised egg’s early division are known—displayed abnormalities. That compared with an abnormality rate of just an eighth in control zygotes grown from untransplanted, healthy eggs.

This discrepancy surprised—and worried—Dr Mitalipov. The abnormality rate he observed was much higher than those seen when the procedure is carried out on other species. That, though, could be because this is the first time it has been attempted with human eggs. Each species has its quirks, and if mitochondrial transplants were to become routine, the quirks of humans would, no doubt, quickly become apparent. With tweaks, they could be fixed, Dr Mitalipov predicts.

However, turning this experiment into a medical procedure would be a long road, and not just scientifically. Dr Mitalipov has little doubt that his zygotes could be brought to term if they were transplanted into a woman’s womb. That experiment, though, is illegal—and, in the view of some, rightly so. But the fact that it now looks possible will surely stimulate debate about whether the law should be changed.

Two kinds of question arise. One kind is pragmatic: would the process usually work and, if it did, would it always lead to a healthy baby who would have a normal chance of growing into a healthy adult? The second kind of question is moral, for what is being proposed is, in essence, genetic engineering. Not, perhaps, as classically conceived because no DNA is artificially modified. But it is engineering nevertheless. And that might worry some people.

On the first kind of question, the auspices are good. When Dr Mitalipov tested his zygotes, he could find no trace of mutated mitochondrial DNA in them, so the purpose of the procedure seems to have been achieved. And an experiment on monkeys that he began three years ago has produced four healthy offspring that are not apparently different from any other young monkey of their age. These are preliminary results, but they are encouraging.

It is on the moral questions that things may stumble. There is no consensus. Some people oppose such genetic tinkering in principle. Some worry about the consequences of a third adult being involved in the traditionally two-person process of parenthood—though the mitochondrial contribution is restricted to genes for energy-processing proteins and is unlikely to have wider ramifications on, say, family resemblance. Some worry that three-parented individuals may themselves be worried by knowledge of their origin. But until recently such questions have been hypothetical. Now they are real. In September, for example, Britain’s Human Fertilisation and Embryology Authority, which deals with such matters, launched a public consultation to discuss the ethics of creating three-parent offspring of the sort Dr Mitalipov proposes. This consultation runs till December 7th and the results will be given to the government in the spring.

In the end, whether three-parent children are permitted will probably depend on the public “uggh!” factor. There was once opposition to in vitro fertilisation, with pejorative terms like “test-tube baby” being bandied about. Now, IVF is routine, and it is routine because it is successful. In the case of mitochondrial transplants what will probably happen is that one country breaks ranks, permits the procedure, and the world will then see the consequences. If they are good, you will never find anyone who will admit to having opposed the transplants in the first place. If they are bad, the phrase “I told you so” will ring from the rafters.

First published in The Economist. Also available in audio here. This article also had an editorial that ran with it.

This story was mentioned on the cover page of the print issue and made it to the front page of  Reddit and Digg, receiving over 250,000 views in two days.

Image credit: The Economist