After open source software, it is now the turn of open source drug research. If this unique process can find a new anti-TB drug, it might well become the future of drug research. G.S. Mudur reports
In the temple town of Thanjavur, Aparna Venkatachalam, a final year engineering student, has turned into a foot soldier in a fresh scientific assault on the microbe that causes tuberculosis. After combing through some 200 research papers and spending dozens of hours searching online biological databases, she has assigned functions — biological tasks — to 60 proteins found in the TB microbe. She picked up a reward for her efforts last week — an Acer Netbook.
Venkatachalam is one of a group of 120 students and researchers scattered across India, Dubai, Japan and Germany, who have put together the most detailed map constructed so far to describe the biochemistry of a living organism. The 18-month science project, spearheaded by India’s Council of Scientific and Industrial Research (CSIR), is seeking new drugs against the TB microbe in a manner never attempted before.
“When you want to destroy an enemy, it’s good to identify vulnerabilities,” said Samir Brahmachari, director general of the CSIR. “This map will provide us unprecedented insights into the biochemistry of the TB micro-organism.”
The search for new drugs against TB is the first project of the CSIR’s Open SourceDrug Discovery (OSDD) programme, a Rs 150 crore effort to solve complex problems by breaking them into smaller “work packets” open to virtually anyone across the scientific community to solve. The challenges are posed on the OSDD website, and researchers wishing to try and tackle them need only to register and join the effort.
An international consortium of scientists had sequenced the genome of the microbe Mycobacterium TB [MTB] nearly 12 years ago. And over the past decade, scientists have identified 3,998 genes, and assigned biological functions to all but nine of them.
The OSDD effort has now generated a map that places about 3,700 MTB genes and their protein products into a network of biochemical pathways. The network, a web of biochemical reactions, shows how these genes and proteins allow MTB to carry out its myriad life-cycle activities — from invading human cells to evading the human immune system to routine housekeeping.
“It’s a very big and a very complex circuit,” said Hiraoki Kitanu, director of the Systems Biology Institute in Japan, who leads a research team that has contributed significantly to the development of a computer-readable format to display models of biological processes, and who has joined the OSDD effort. “This is a new approach for drug discovery,” Kitanu said.
Scientists believe MTB is an appropriate organism to pit innovative ideas against. This killer microbe claims about 1,000 lives across India each day. The four best anti-TB drugs that make up the first line of therapy were developed in the 1950s and 1960s. Secondary drugs are toxic and expensive. There are now drug-resistant versions of MTB, which pose a new challenge. While clinical trials are under way, a new drug is not expected to be ready for use until 2012.
All previous efforts at finding drugs to fight MTB involved a laborious trial-and-error method in which researchers exposed the organism to compounds and picked the ones that appeared most effective in killing bacteria or suppressing their growth. Researchers believe that the map of biochemical pathways will now allow them to choose specific regions of the pathway as targets for future drugs. “Instead of shooting in the dark, we’ll be searching for targets in a rational way,” said Anshu Bharadwaj, a scientist at the Institute of Genomics and Integrative Biology, New Delhi, who, among other roles, also assigns work packets to OSDD researchers.
Some 800 researchers — most of them students — joined the effort, but only some 120 who succeeded in assigning functions to at least 40 genes — Venkatachalam among them — were picked to receive the reward. One of them was a homemaker from Dubai who had used her skills in bioinformatics to help build the pathways map. All those who won a reward, however, did not attend the meeting in Delhi — a software engineer from Germany told the OSDD that he doesn’t travel as he is wheelchair bound.
Venkatachalam, a bioinformatics student at SASTRA University in Thanjavur, and her colleague Ahalyaa Subramanian scanned published scientific literature to tell the stories of 60 MTB genes. In all, Brahmachari estimates, the consortium of researchers scanned at least 12,000 research papers on TB and compiled the information in a standardised format to build the map.
Some biologists caution people not to expect a new drug too soon. “I’m very optimistic this is going to have an impact,” said Richard Jefferson, a molecular biologist based in Australia and chief executive officer of Cambia, a non-profit institute seeking to promote innovation. “But it’s important we do not expect too much too soon. It’s going to be a long fight,” Jefferson said at the OSDD meeting last week.
In the drug discovery process, scientists will have to look for “vulnerabilities” in MTB pathways that can be exploited to design a new drug. Researchers say that one of the biggest challenges will be to find compounds that act exclusively on MTB. “We’ll need to find a vulnerability exclusive to MTB that leaves the human system alone,” said Bharadwaj.
Brahmachari himself has ventured to suggest that the effort could lead to a new candidate drug ready for clinical trials within two years. If that happens, said Brahmachari, the OSDD will invite five drug companies to invest four per cent of drug development costs, while the CSIR will provide the remainder 80 per cent. Each company would then get an opportunity to produce inexpensive generic versions of the drug.
If the OSDD does indeed deliver a new and effective drug for TB, it might trigger a paradigm change in drug research.
Cat scratch disease (CSD) is a bacterial disease caused by Bartonella henselae. Most children with CSD have been bitten or scratched by a cat and developed a mild infection at the point of injury. Lymph nodes, especially those around the head, neck, and upper limbs, become swollen. Additionally, a youngster with CSD may experience fever, headache, fatigue, and a poor appetite.
Can my cat transmit Bartonella henselae to me?
Sometimes, yes, cats can spread B. henselae to people. Most people get CSD from cat bites and scratches. Kittens are more likely to be infected and to pass the bacterium to people. About 40% of cats carry B. henselae at some time in their lives. Cats that carry B. henselae do not show any signs of illness; therefore, parents cannot tell which cats can spread the disease to you. children with immunocompromised conditions, such as those undergoing immunosuppressive treatments for cancer, organ transplant patients, and children with HIV/AIDS, are more likely than others to have complications of CSD. Although B. henselae has been found in fleas, so far there is no evidence that a bite from an infected flea can give you CSD.
How can I reduce my child’s risk of getting cat scratch disease from my cat?
Avoid “rough play” with cats, especially kittens. This includes any activity that may lead to cat scratches and bites.
Wash cat bites and scratches immediately and thoroughly with running water and soap.
Do not allow cats to lick open wounds that your child may have.
If your child develops an infection (with pus and pronounced swelling) where they were scratched or bitten by a cat or develop symptoms, including fever, headache, swollen lymph nodes, and fatigue, contact your child’s physician.
Swollen glands a Common Occurrence :
Most adults know that an unexplained lump is one of the seven warning signs of cancer. So it is easy to understand why discovering an enlarged lymph node in their childâ€™s neck or under their arm strikes fear in a parent’s heart. They suspect the worst and arrange a prompt visit with their youngster’s physician. True, enlarged lymph nodes can be a symptom of a serious disease, but in children that is rarely the case.
Made up of specialized blood cells, lymph nodes are an important part of the bodyâ€™s defense system. There are nearly 1,000 of them stationed throughout the body, ranging in size from a pinhead to a small grape. Nodes act as filtering plants for the lymph system, trapping and eliminating foreign particles and infectious agents from the circulation. In addition, lymph nodes act to prevent the spread of infection by producing white blood cells and antibodies to destroy infecting germs and poisons. When lymph nodes enlarge, it usually means that the nodes are being called into action to make extra antibody or are filtering out unfriendly germs. Any illness or wound, even one as minor as an insect bite, can mobilize this response, which explains why children’s nodes can be swollen even when the youngster does not seem sick.
The lymph node system is divided into different districts with each part of the body being defended by its own network of nodes. Most of the time, the location of the enlaged node indicates where the current or past infection was located. For example, since most infections enter the child’s body through the nose, mouth, and throat, the lymph nodes in the neck (especially the ones just under the corner of the jaw bone) are most often swollen and tender. When a child has an infection in the arm, the nodes under the arm will enlarge. Similarly, swollen nodes found in the groin usually indicate an infection in the leg. Certain viral infections, like infectious mononucleosis, can cause swelling of the lymph nodes all over the body. Occasionally, the node itself can become infected causing skin redness, node tenderness, and in rare cases a yellow discharge is seen oozing from the lump. When this occurs, parents should contact the child’s physician since antibiotics will probably be needed.
Because less fat covers the lymph nodes in children, they are very easy to feel, even when they are not busy filtering germs or making antibody. Furthermore, a youngstes nodes enlarge faster and get bigger in response to an infection and stay swollen longer, “like a peace keeping force that remains behind after the battles have all been fought,” according to California pediatrician Dr. Gilbert Simon. “They both seem to last a lot longer than would appear necessary.”
When a child’s lymph nodes enlarge without an obvious reason, infections such as mononucleosis, tuberculosis, and a number of viruses, may be responsible. Another cause of lymph node swelling is a common condition called “Cat-Scratch Disease” that follows weeks to months after a scratch from a cat (most often a kitten).
Still, the major concern for most parents when they feel a lymph node in their child is leukemia or Hodgkin’s Disease. Physicians also think about this possibility, and use child’s physical examination to help determine whether an enlarged node is worrisome or not.
The first important finding is the gland’s location – lymph nodes in the neck are less likely to be a problem than those found above the collarbone, for example. A node that is growing rapidly is potentially more serious than one that remains the same size for a period of time. Physicians are less concerned about a swollen node when the cause is found, such as a past ear or throat infection. Generally, a lymph gland that is easily movable and can be rolled around under the skin is less likely to be caused by a serious disease. The size of the lymph node is usually a poor indicator of its cause, but a node that is abnormally large should always be carefully watched. While all nodes in children feel like firm rubber, an extremely hard lymph node might be more cause for concern. The last sign doctors look for has more to do with the child than node. Lymph node swelling that persists while the child begins experiencing intermittent fevers, weight loss, night sweats, fatigue, or loss of appetite requires a more intensive investigation.
Occasionally, a two-week trial of antibiotics will help determine whether or not a swollen lymph node is worrisome. If the node responds to medication by getting smaller, an infection is most likely the cause. Failure of the lymph node to get smaller may mean followup observation perhaps additional studies. Investigations might include a blood count, skin test for tuberculosis and cat-scratch disease, throat culture, chest x-ray and a mononucleosis test.
A physician might consider a biopsy of the lymph node if the swelling persists without an apparent diagnosis. Fortunately, most biopsies do not reveal cancer but reassure both the family and physician that the condition is not malignant. It can also help in making the diagnosis!
Doctors caring for kids frequently exam their young patients after a parent discovers a swollen lymph node. Since young children are more suscpetible to infections than older kids and adults, enlarged nodes are very common. However, whenever a parent is worried after finding a lump in their child, they should check with their pediatrician, just for safety sake.
Swollen Glands Rarely Serious :- Discovering a bump in your young childâ€™s neck or under their arm can strike fear into the hearts of parents. True, this can be the sign of a serious illness such as cancer or tuberculosis, but that’s rarely the case. Children quite often have visible enlarged glands, especially in their necks, and most of the time the swelling indicates the presence of an infection of some kind. Every wonder what are these “swollen glands?” Think back to the last time that you were sick and visited your doctor. If your memory is good, you might recall the doctor carefully palpated all sides of your neck. More than just to soothe a tense patient, this exam provided important clues for your doctor about the body’s current “battle readiness” in the war against infections diseases.
Swollen glands are, in fact, specialized tissue called lymph nodes. There are more than a thousand lymph nodes scattered throughout the body, ranging in size from a pinhead to a small grape. These glands consist of a dense core of cells that serve as a “staging area” for the body’s fight against disease by producing white blood cells and antibodies. The lymph glands also filter out impurities in the body such as germs and foreign proteins. The glands in young children are covered with less tissue and fat than in adults, and so are more visible. When a physician feels a swollen node on physical examination, it usually infers the possibility of some infectious process at work.
In children, swollen lymph nodes are usually due to viral illnesses. Another frequent cause of enlerged glands in children is “Cat Scratch Disease.” The course of children with “Cat-Scratch Disease” is fairly consistent; several weeks to months after a scratch or bite from a cat, the lymph glands that drain the scratch site become enlarged and tender. For example, if the scratch is on the hands or arms, the lymph glands under the arm or in the neck become swollen. Likewise, the lymph glands in the groin enlarge if the cat scratch was on the leg. Additionally, the skin over the enlarged gland(s) may become red and warm. Usually by the time the lymph glands become enlarged, the primary scratch site has completely healed over. The child is otherwise healthy; rarely are there other symptoms present, such as headache, fever, persistent fatigue, or a sore throat.
“Cat-Scratch Disease” was first described by doctors in the 1930â€™s and is primarily a pediatric disease, with 80% of cases occurring in persons under 21 years of age. Over 90% of the children have been exposed to a healthy cat, usually a kitten (since adult cats are probably smart enough to stay away from kids!). Boys have a higher chance of getting the disease, perhaps because they tend to be more aggressive when playing with their pets. Interestingly, 25% of children cannot recall actually being scratched by a cat! The incubation period of the disease is usually 7 to 12 days after exposure, but it can be as long as three months. Person to person transmission has not been reported. The actual cause of “Cat-Scratch Disease” is unknown, but investigators have recently isolated what appears to be a previously unknown bacteria at the site of the infections. More research will be necessary to better define the disease and to then develop appropriate treatment.
The diagnosis of “Cat-Scratch Disease” is usually made by a history of exposure to a cat, an inoculation or scratch site, and a physical examination of the child. While there is a definite test to confirm the diagnosis it is not readily available to most practicing physicians. Since enlarged lymph nodes can be caused by other medical conditions, your childâ€™s doctor may order other tests, such as a tuberculosis skin test, blood tests, chest x-rays, or even a biopsy of the lymph gland itself.
Prevention of “Cat-Scratch Disease” is difficult; there are over 50 million cats in the United States and cases of “Cat-Scratch Disease” can occur even though a cat has been declawed. Parents should teach their children to avoid bites and scratches, and not to allow a cat to lick open skin wounds on the child. Parents of a young child with “Cat-Scratch Disease” frequently ask about permanent removal of the animal from the home, but this is unnecessary. The cat who transmits “Cat-Scratch Disease” is not sick (Veterinarians are presently unable to test cats for this illness) and the disease confers lifelong immunity to the child. This means that each child will only be stricken once by the disease. Furthermore, not every child who gets scratched by a cat will get the illness. Because there has never been a case of child-to-child transmission, isolation from other siblings or playmates is unnecessary.
Parents need to help their children through the extended recovery period, which may be as long as five months. Treatment includes acetaminophen for fever and ibuprofen for pain. Hot, salt water compresses on the involved glands have been known to shorten the duration of lymph gland enlargement. Rough-housing and contact sports should probably be avoided until the glands are no longer tender. In some cases, the involved lymph glands may need to be sampled by needle aspiration by a surgeon to insure that other diseases are not present. This is usually done if the gland becomes extremely painful and disabling to the child. The long term outlook for children with “Cat-Scratch Disease” is similar to other common infectious diseases in children, with little long term effects persisting into adulthood. Parents whose households also include cats as pets should be on the look out for swollen glands in their children, for this may be a tip-off to this common and relatively harmless disease caused by a cat scratch.