All Articles by Dwaipayan Mukherjee

5 Articles

Understanding Biology through Computational Models

The Human body is the most complex machinery known to man. From the genetic material to the tissues and organs, every part of the machine works in absolute synergy on a daily basis.

However, the body also faces daily assaults from a host of chemicals and agents in the environment, be it at home, in school, or in the workplace. Some of these chemicals are in our food or drugs that we take, and some others get in our body inadvertently through the air we breathe, or the things we touch. Sometimes, these chemicals cause unwanted outcomes in our bodies – either short terms or long term. Even the drugs we take or the food we eat for beneficial effects might have unwanted reactions which might affect our health.

Biological and health research has come a long way in giving us many of the answers we seek regarding deleterious health effects. However, with new chemicals, drugs, and cosmetics entering the market every day, the problem of understanding human health risks is a constant one, which changes with every new challenge. Computational and mathematical models help in leveraging existing biological knowledge using fast computers and efficient algorithms to produce novel insights into these complicated problems.

Toxicokinetic Modeling

PBPK Modeling

PBPK-CCLPhysiologically Based Pharmacokinetic (PBPK) Modeling is being applied more and more to provide whole-body level insights to chemical absorption-distribution-metabolism-extraction (ADME) within the body. PBPK models (often referred to as PBTK models when applied to toxic chemicals) are widely used in the pharmaceutical industry for Model Based Drug Development as well as for chemical risk analysis by regulatory agencies like the EPA and the FDA.

Historically, PBPK models were first developed by chemical engineers who saw the human body as analogous to the network of pipes and reactors which they were accustomed to.  PBPK models bring together knowledge of biology, chemistry, mathematics to often produce models of immense complexity.

Specific projects utilizing PBPK models:

 

Figure reference: Xue et al., Probabilistic Modeling of Dietary Arsenic Exposure and Dose and Evaluation with 2003-2004 NHANES Data, Environ. Health. Perspect. (2009); 118, 345-350.

Nanoparticle Toxicodynamics

“Toxicokinetics is what the body does to the chemicals, while toxicodynamics is what the chemicals do to the body.”

alveolus2Traditional PBPK models look at the entire human body from a physiome level. On the other hand, toxicodynamic or pharmacodynamic models generally focus on a particular organ or organ system and try to ascertain the changes occurring at that scale. Shown alongside is an example of a toxicodynamic (TD) model looking at the alveolar sub-system which is part of the lung. The alveolar system is responsible for protection of the body against inhaled foreign chemicals and particles. Any environmental particulate or inhaled drug encounters this system and causes dynamic changes to the functioning of the system often leading to immune responses. The final outcome of the foreign chemical depends largely on the processes outlined in the figure.

Specific projects:

Biological pathway modeling

Utilizing network models to model complex biological pathways

 

Most biological processes take place as a result of a complex set of processes connected by networks of cellular signals. These cellular signals consist of signaling molecules secreted by cells and cell organelles. The behavior of any biological process we see and feel every day is an ensemble of a number of these biological pathways.

Specific projects:

  • Analyzing oxidative stress in liver cells
  • Understanding effects of xenobiotic mycoestrogens on estrogenic pathways

Modeling health effects in vulnerable populations

Modeling population-wide health effects and risks

Just as a human body presents an enthralling level of complexity, so does a human population present a staggering level of variety. Each human being is very different for another in the way the body responds to a certain chemical. One man’s drug is another man’s poison.

PBPK models predicting chemical kinetics in the body would be incomplete if they did not capture the characteristic differences and variety among individuals pertaining to ADME of the chemical.

Specific projects:

  • Modeling population-wide exposure and intake of manufactured nanomaterials in the US population
  • Analyzing linkages between chemical exposure risk and neurotoxicity in the US population