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Deep Learning for the Life Sciences by Vijay Pande, Patrick Walters, Peter Eastman, Bharath Ramsundar

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Chapter 1. Why Life Science?

While there are many directions that those with a technical inclination and a passion for data can pursue, few areas can match the fundamental impact of biomedical research. The advent of modern medicine has fundamentally changed the nature of human existence. Over the last 20 years, we have seen innovations that have transformed the lives of countless individuals. When it first appeared in 1981, HIV/AIDS was a largely fatal disease. Continued development of antiretroviral therapies has dramatically extended the life expectancy for patients in the developed world.  Other diseases, such as hepatitis C, which was considered largely untreatable a decade ago, can now be cured. Advances in genetics are enabling the identification and, hopefully soon, the treatment of a wide array of diseases. Innovations in diagnostics and instrumentation have enabled physicians to specifically identify and target disease in the human body. Many of these breakthroughs have benefited from and will continue to be advanced by computational methods.

Why Deep Learning?

Machine learning algorithms are now a key component of everything from online shopping to social media. Teams of computer scientists are developing algorithms that enable digital assistants such as the Amazon Echo or Google Home to understand speech. Advances in machine learning have enabled routine on-the-fly translation of web pages between spoken languages. In addition to machine learning’s impact on everyday life, it has impacted many areas of the physical and life sciences. Algorithms are being applied to everything from the detection of new galaxies from telescope images to the classification of subatomic interactions at the Large Hadron Collider.

One of the drivers of these technological advances has been the development of a class of machine learning methods known as deep neural networks. While the technological underpinnings of artificial neural networks were developed in the 1950s and refined in the 1980s, the true power of the technique wasn’t fully realized until advances in computer hardware became available over the last 10 years. We will provide a more complete overview of deep neural networks in the next chapter, but it is important to acknowledge some of the advances that have occurred through the application of deep learning:

  • Many of the developments in speech recognition that have become ubiquitous in cell phones, computers, televisions, and other internet-connected devices have been driven by deep learning.

  • Image recognition is a key component of self-driving cars, internet search, and other applications. Many of the same developments in deep learning that drove consumer applications are now being used in biomedical research, for example, to classify tumor cells into different types.

  • Recommender systems have become a key component of the online experience. Companies like Amazon use deep learning to drive their “customers who bought this also bought” approach to encouraging additional purchases. Netflix uses a similar approach to recommend movies that an individual may want to watch. Many of the ideas behind these recommender systems are being used to identify new molecules that may provide starting points for drug discovery efforts.

  • Language translation was once the domain of very complex rule-based systems. Over the last few years, systems driven by deep learning have outperformed systems that had undergone years of manual curation. Many of the same ideas are now being used to extract concepts from the scientific literature and alert scientists to journal articles that they may have missed.

These are just a few of the innovations that have come about through the application of deep learning methods. We are at an interesting time when we have a convergence of widely available scientific data and methods for processing that data. Those with the ability to combine data with new methods for learning from patterns in that data can make significant scientific advances.

Contemporary Life Science Is About Data

As mentioned previously, the fundamental nature of life science has changed. The availability of robotics and miniaturized experiments has brought about dramatic increases in the amount of experimental data that can be generated. In the 1980s a biologist would perform a single experiment and generate a single result. This sort of data could typically be manipulated by hand with the possible assistance of a pocket calculator. If we fast-forward to today’s biology, we have instrumentation that is capable of generating millions of experimental data points in a day or two. Experiments like gene sequencing, which can generate huge datasets, have become inexpensive and routine.

The advances in gene sequencing have led to the construction of databases that link an individual’s genetic code to a multitude of health-related outcomes, including diabetes, cancer, and genetic diseases such as cystic fibrosis. By using computational techniques to analyze and mine this data, scientists are developing an understanding of the causes of these diseases and using this understanding to develop new treatments.

Disciplines that once relied primarily on human observation are now utilizing datasets that simply could not be analyzed manually. Machine learning is now routinely used to classify images of cells. The output of these machine learning models is used to identify and classify cancerous tumors and to evaluate the effects of potential disease treatments.

Advances in experimental techniques have led to the development of several databases that catalog the structures of chemicals and the effects that these chemicals have on a wide range of biological processes or activities. These structure–activity relationships (SARs) form the basis of a field known as chemical informatics, or cheminformatics. Scientists mine these large datasets and use the data to build predictive models that will drive the next generation of drug development.

With these large amounts of data comes a need for a new breed of scientist who is comfortable in both the scientific and computational domains. Those with these hybrid capabilities have the potential to unlock structure and trends in large datasets and to make the scientific discoveries of tomorrow.

What Will You Learn?

In the first few chapters of this book, we provide an overview of deep learning and how it can be applied in the life sciences. We begin with machine learning, which has been defined as “the science (and art) of programming computers so that they can learn from data.”1

Chapter 2 provides a brief introduction to deep learning. We begin with an example of how this type of machine learning can be used to perform a simple task like linear regression, and progress to more sophisticated models that are commonly used to solve real-world problems in the life sciences. Machine learning typically proceeds by initially splitting a dataset into a training set that is used to generate a model and a test set that is used to assess the performance of the model. In Chapter 2 we discuss some of the details surrounding the training and validation of predictive models. Once a model has been generated, its performance can typically be optimized by varying a number of characteristics known as hyperparameters. The chapter provides an overview of this process. Deep learning is not a single technique, but a set of related methods. Chapter 2 concludes with an introduction to a few of the most important deep learning variants.

In Chapter 3, we introduce DeepChem, an open source programming library that has been specifically designed to simplify the creation of deep learning models for a variety of life science applications. After providing an overview of DeepChem, we introduce our first programming example, which demonstrates how the DeepChem library can be used to generate a model for predicting the toxicity of molecules. In a second programming example, we show how DeepChem can be used to classify images, a common task in modern biology. As briefly mentioned earlier, deep learning is used in a variety of imaging applications, ranging from cancer diagnosis to the detection of glaucoma. This discussion of specific applications then motivates an explanation of some of the inner workings of deep learning methods.

Chapter 4 provides an overview of how machine learning can be applied to molecules. We begin by introducing molecules, the building blocks of everything around us. Although molecules can be considered analogous to building blocks, they are not rigid. Molecules are flexible and exhibit dynamic behavior. In order to characterize molecules using a computational method like deep learning, we need to find a way to represent molecules in a computer. These encodings can be thought of as similar to the way in which an image can be represented as a set of pixels. In the second half of Chapter 4, we describe a number of ways that molecules can be represented and how these representations can be used to build deep learning models.

Chapter 5 provides an introduction to the field of biophysics, which applies the laws of physics to biological phenomena. We start with a discussion of proteins, the molecular machines that make life possible. A key component of predicting the effects of drugs on the body is understanding their interactions with proteins. In order to understand these effects, we begin with an overview of how proteins are constructed and how protein structures differ. Proteins are entities whose 3D structure dictates their biological function. For a machine learning model to predict the impact of a drug molecule on a protein’s function, we need to represent that 3D structure in a form that can be processed by a machine learning program. In the second half of Chapter 5, we explore a number of ways that protein structures can be represented. With this knowledge in hand, we then review another code example where we use deep learning to predict the degree to which a drug molecule will interact with a protein.

Genetics has become a key component of contemporary medicine. The genetic sequencing of tumors has enabled the personalized treatment of cancer and has the potential to revolutionize medicine. Gene sequencing, which used to be a complex process requiring huge investments, has now become commonplace and can be routinely carried out. We have even reached the point where dog owners can get inexpensive genetic tests to determine their pets’ lineage. In Chapter 6, we provide an overview of genetics and genomics, beginning with an introduction to DNA and RNA, the templates that are used to produce proteins. Recent discoveries have revealed that the interactions of DNA and RNA are much more complex than originally believed. In the second half of Chapter 6, we present several code examples that demonstrate how deep learning can be used to predict a number of factors that influence the interactions of DNA and RNA.

Earlier in this chapter, we alluded to the many advances that have come about through the application of deep learning to the analysis of biological and medical images. Many of the phenomena studied in these experiments are too small to be observed by the human eye. In order to obtain the images used with deep learning methods, we need to utilize a microscope. Chapter 7 provides an overview of microscopy in its myriad forms, ranging from the simple light microscope we all used in school to sophisticated instruments that are capable of obtaining images at atomic resolution. This chapter also covers some of the limitations of current approaches, and provides information on the experimental pipelines used to obtain the images that drive deep learning models.

One area that offers tremendous promise is the application of deep learning to medical diagnosis. Medicine is incredibly complex, and no physician can personally embody all of the available medical knowledge. In an ideal situation, a machine learning model could digest the medical literature and aid medical professionals in making diagnoses. While we have yet to reach this point, a number of positive steps have been made. Chapter 8 begins with a history of machine learning methods for medical diagnosis and charts the transition from hand-encoded rules to statistical analysis of medical outcomes. As with many of the topics we’ve discussed, a key component is representing medical information in a format that can be processed by a machine learning program. In this chapter, we provide an introduction to electronic health records and some of the issues surrounding these records. In many cases, medical images can be very complex and the analysis and interpretation of these images can be difficult for even skilled human specialists. In these cases, deep learning can augment the skills of a human analyst by classifying images and identifying key features. Chapter 8 concludes with a number of examples of how deep learning is used to analyze medical images from a variety of areas.

As we mentioned earlier, machine learning is becoming a key component of drug discovery efforts. Scientists use deep learning models to evaluate the interactions between drug molecules and proteins. These interactions can elicit a biological response that has a therapeutic impact on a patient. The models we’ve discussed so far are discriminative models. Given a set of characteristics of a molecule, the model generates a prediction of some property. These predictions require an input molecule, which may be derived from a large database of available molecules or may come from the imagination of a scientist. What if, rather than relying on what currently exists, or what we can imagine, we had a computer program that could “invent” new molecules? Chapter 9 presents a type of deep learning program called a generative model. A generative model is initially trained on a set of existing molecules, then used to generate new molecules. The deep learning program that generates these molecules can also be influenced by other models that predict the activity of the new molecules.

Up to now, we have discussed deep learning models as “black boxes.” We present the model with a set of input data and the model generates a prediction, with no explanation of how or why the prediction was generated. This type of prediction can be less than optimal in many situations. If we have a deep learning model for medical diagnosis, we often need to understand the reasoning behind the diagnosis. An explanation of the reasons for the diagnosis will provide a physician with more confidence in the prediction and may also influence treatment decisions. One historic drawback to deep learning has been the fact that the models, while often reliable, can be difficult to interpret. A number of techniques are currently being developed to enable users to better understand the factors that led to a prediction. Chapter 10 provides an overview of some of these techniques used to enable human understanding of model predictions. Another important aspect of predictive models is the accuracy of a model’s predictions. An understanding of a model’s accuracy can help us determine how much to rely on that model. Given that machine learning can be used to potentially make life-saving diagnoses, an understanding of model accuracy is critical. The final section of Chapter 10 provides an overview of some of the techniques that can be used to assess the accuracy of model predictions.

In Chapter 11 we present a real-world case study using DeepChem. In this example, we use a technique called virtual screening to identify potential starting points for the discovery of new drugs. Drug discovery is a complex process that often begins with a technique known as screening. Screening is used to identify molecules that can be optimized to eventually generate drugs. Screening can be carried out experimentally, where millions of molecules are tested in miniaturized biological tests known as assays, or in a computer using virtual screening. In virtual screening, a set of known drugs or other biologically active molecules is used to train a machine learning model. This machine learning model is then used to predict the activity of a large set of molecules. Because of the speed of machine learning methods, hundreds of millions of molecules can typically be processed in a few days of computer time.

The final chapter of the book examines the current impact and future potential of deep learning in the life sciences. A number of challenges for current efforts, including the availability and quality of datasets, are discussed. We also highlight opportunities and potential pitfalls in a number of other areas including diagnostics, personalized medicine, pharmaceutical development, and biology research.

1 Furbush, James. “Machine Learning: A Quick and Simple Definition.” https://www.oreilly.com/ideas/machine-learning-a-quick-and-simple-definition. 2018.

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