Engineer Better Medicines

Doctors have long known that people differ in susceptibility to disease and response to medicines. But, with little guidance for understanding and adjusting to individual differences, treatments developed have generally been standardized for the many, rather than the few.

How will genetic science change how medicines are made?

Human DNA contains more than 20,000 genes, all of which are stored in our cells' nuclei. A gene is a strand of chemical code, a sort of blueprint for proteins and other substances necessary for life. Cells make those molecules according to the genetic blueprints.

Each person’s overall blueprint is basically the same, made up of about 3 billion “letters” of code, each letter corresponding to a chemical subunit of the DNA molecule. But subtle variants in about 1 percent of our DNA — often the result of just a single chemical letter being different — give humans their individual identities.

Beyond physical appearance, genes give rise to distinct chemistries in various realms of the body and brain. Such differences sometimes predispose people to particular diseases, and some dramatically affect the way a person will respond to medical treatments.

Ideally, doctors would be able to diagnose and treat people based on those individual differences, a concept commonly referred to as “personalized medicine.” At its core, personalized medicine is about combining genetic information with clinical data to optimally tailor drugs and doses to meet the unique needs of an individual patient. Eventually, personalized medicine will be further informed by detailed understanding of the body’s distinct repertoire of proteins (proteomics) and complete catalog of biochemical reactions (metabolomics).

“Personalized medicine,” writes Lawrence Lesko of the U.S. Food and Drug Administration, “can be viewed . . . as a comprehensive, prospective approach to preventing, diagnosing, treating, and monitoring disease in ways that achieve optimal individual health-care decisions.” [Lesko p. 809]                      

Already, some aspects of the personalized medicine approach are in place for some diseases. Variants of a gene linked to breast cancer, for instance, can foretell a woman’s likely susceptibility to developing or surviving the disease, a helpful guide for taking preventive measures. In certain cases of breast cancer, the production of a particular protein signals a more aggressive form of the disease that might be more effectively controlled with the drug Herceptin.

Still, multiple challenges remain in the quest for a widespread effective system of personalized medicine. They will be addressed by the collaborative efforts of researchers from many disciplines, from geneticists to clinical specialists to engineers.

What prevents you from creating personalized medicines now?

One engineering challenge is developing better systems to rapidly assess a patient’s genetic profile; another is collecting and managing massive amounts of data on individual patients; and yet another is the need to create inexpensive and rapid diagnostic devices such as gene chips and sensors able to detect minute amounts of chemicals in the blood.

In addition, improved systems are necessary to find effective and safe drugs that can exploit the new knowledge of differences in individuals. The current “gold standard” for testing a drug’s worth and safety is the randomized controlled clinical trial -- a study that randomly assigns people to a new drug or to nothing at all, a placebo, to assess how the drug performs. But that approach essentially decides a drug’s usefulness based on average results for the group of patients as a whole, not for the individual.     

New methods are also needed for delivering personalized drugs quickly and efficiently to the site in the body where the disease is localized. For instance, researchers are exploring ways to engineer nanoparticles that are capable of delivering a drug to its target in the body while evading the body’s natural immune response. Such nanoparticles could be designed to be sensitive to the body’s internal conditions, and therefore could, for example, release insulin only when the blood’s glucose concentration is high.

In a new field called “synthetic biology,” novel biomaterials are being engineered to replace or aid in the repair of damaged body tissues. Some are scaffolds that contain biological signals that attract stem cells and guide their growth into specific tissue types. Mastery of synthetic tissue engineering could make it possible to regenerate tissues and organs.

What are the benefits of personalized medicine?

Ultimately, the personalization of medicine should have enormous benefits. It ought to make disease (and even the risk of disease) evident much earlier, when it can be treated more successfully or prevented altogether. It could reduce medical costs by identifying cases where expensive treatments are unnecessary or futile. It will reduce trial-and-error treatments and ensure that optimum doses of medicine are applied sooner. Most optimistically, personalized medicine could provide the path for curing cancer, by showing why some people contract cancer and others do not, or how some cancer patients survive when others do not.

Of course, a transition to personalized medicine is not without its social and ethical problems. Even if the technical challenges can be met, there are issues of privacy when unveiling a person’s unique biological profile, and there will likely still be masses of people throughout the world unable to access its benefits deep into the century. 

How do you fight drug-resistant infections?

The war against infectious agents has produced a powerful arsenal of therapeutics, but treatment with drugs can sometimes exacerbate the problem. By killing all but the drug-resistant strains, infectious agents that are least susceptible to drugs survive to infect again. They become the dominant variety in the microbe population, a present-day example of natural selection in action. This leads to an ever-present concern that drugs can be rendered useless when the microbial world employs the survival-of-the-fittest strategy of evolution.  And frequently used drugs contribute to their own demise by strengthening the resistance of many enemies.

“Drug-resistant pathogens — whether parasites, bacteria, or viruses — can no longer be effectively treated with common anti-infective drugs,” writes David L. Heymann of the World Health Organization.

A healthy future for the world’s population will depend on engineering new strategies to overcome multiple drug resistances.

One major challenge in this endeavor will be to understand more fully how drug resistance comes about, how it evolves, and how it spreads. Furthermore, the system for finding and developing new drugs must itself evolve and entirely novel approaches to fighting pathogens may be needed also.

Drug resistance is nothing new. The traditional approach to this problem, still potentially useful, is expanding the search for new antibiotics. Historically, many drugs to fight disease-producing microbes have been found as naturally occurring chemicals in soil bacteria. That source may yet provide promising candidates. Even more drug candidates, though, may be available from microbes in more specialized ecological niches or from plants or from bacteria living in remote or harsh environments (e.g. deep lakes and oceans).

Bacteria that live symbiotically with insects, for instance, may offer novel chemical diversity for anti-infective drug searches. Plants provide many interesting compounds with anti-bacterial properties, and genetic manipulation can be used to devise variants of those compounds for testing. And chemical engineers may still be able to create entirely new classes of drug candidate molecules from scratch in the laboratory.

Further strategies involve directing specific counterattacks at the infectious agents’ resistance weapons. Treatments can be devised that combine an antibiotic with a second drug that has little antibiotic effect but possesses the power to disarm a bacterial defense molecule. Other hybrid treatments could be devised using compounds that impair the invading pathogen’s ability to pump the antibiotic component out of the bacterial cell.      

The drug-resistance problem is not limited to bacteria and antibiotics — anti-viral drugs for fighting diseases such as AIDS and influenza face similar problems from emerging strains of resistant viruses. In fact, understanding the development of resistance in viruses is especially critical for designing strategies to prevent pandemics. The use of any anti-microbial drug must be weighed against its contribution to speeding up the appearance of resistant strains.

What is engineering's role in creating personalized medicine?

The engineering challenges for enabling drug discovery mirror those needed to enable personalized medicine: development of more effective tools and techniques for rapid analysis and diagnosis so that a variety of drugs can be quickly screened and proper treatments can be promptly applied. Current drugs are often prescribed incorrectly or unnecessarily, promoting the development of resistance without real medical benefit.

Quicker, more precise diagnoses may lead to more targeted and effective therapies. Antibiotics that attack a wide range of bacteria have typically been sought, because doctors could not always be sure of the precise bacterium causing an infection. Instruments that can determine the real culprit right away could lead to the use of more narrowly targeted drugs, reducing the risk of promoting resistance. Developing organism-specific antibiotics could become one of the century’s most important biomedical engineering challenges.

This could be especially challenging in the case of biological agents specifically designed to be weapons. A system must be in place to rapidly analyze their methods of attacking the body and quickly produce an appropriate medicine. In the case of a virus, small molecules might be engineered to turn off the microbe’s reproductive machinery. Instructions for making proteins are stored by genes in DNA. Another biochemical molecule, called “messenger RNA,” copies those instructions and carries them to the cell’s protein factories. Sometimes other small RNA molecules can attach to the messenger RNA and deactivate it, thereby preventing protein production by blocking the messenger, a process known as RNA interference. Viruses can be blocked by small RNAs in the same manner, if the proper small RNAs can be produced to attach to and deactivate the molecules that reproduce the virus. The key is to decipher rapidly the sequence of chemicals comprising the virus so that effective small RNA molecules can be designed and deployed.

Traditional vaccines have demonstrated the ability to prevent diseases, and even eradicate some such as smallpox. It may be possible to design vaccines to treat diseases as well. Personalized vaccines might be envisioned for either use. But, more effective and reliable manufacturing methods are needed for vaccines, especially when responding to a need for mass immunization in the face of a pandemic.

References

Erwin P. Bottinger, “Foundations, Promises, and Uncertainties of Personalized Medicine,” Mount Sinai Journal of Medicine 74 (2007), pp. 15-21.

Manfred Dietel and Christine Sers, “Personalized medicine and development of targeted therapies: The upcoming challenge for diagnostic molecular pathology. A review,” Virchows Arch 448 (2006), pp. 744-755.

David L. Heymann, “Resistance to Anti-Infective Drugs and the Threat to Public Health,” Cell 124 (February 24, 2006), pp. 671-675. DOI 10.1016/j.cell.2006.02.009.

W. Kalow, “Pharmacogenetics and pharmacogenomics: Origin, status, and the hope for personalized medicine,” The Pharmacogenomics Journal 6 (2006), pp. 162-165. doi:10.1038/sj.tpj.6500361

L.J. Lesko, “Personalized Medicine: Elusive Dream or Imminent Reality?” Clinical Pharmacology & Therapeutics 81 (June 2007), pp. 807-816.

M.P. Lutolf and J.A. Hubbell, “Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering,” Nature Biotechnology 23 (January 2005), pp. 47-55.

Gerard D. Wright and Arlene D. Sutherland, “New strategies for combatingmultidrug-resistant bacteria,” Trends in Molecular Medicine 13 (2007), pp. 260-267. doi:10.1016/j.molmed.2007.04.004.

Mike West et al., “Embracing the complexity of genomic data for personalized medicine,” Genome Research 16 (2006), pp. 559-566.